Use of pyrazolopyridines as therapeutic compounds

ABSTRACT

The present invention provides methods for the treatment or prophylaxis of viral infections such as herpes viral infections.

BACKGROUND OF THE INVENTION

The present invention relates to the use of certain pyrazolopyridinecompounds in therapy. More particularly, the present invention relatesto the use of these compounds compounds for the prophylaxis andtreatment of herpes viral infections.

Of the DNA viruses, those of the herpes group are the sources of themost common viral illnesses in man. The group includes herpes simplexvirus types 1 and 2 (HSV), varicella zoster virus (VZV), cytomegalovirus(CMV), Epstein-Barr virus (EBV), human herpes virus type 6 (HHV-6),human herpes virus type 7 (HHV-7) and human herpes virus type 8 (HHV-8).HSV-1 and HSV-2 are some of the most common infectious agents of man.Most of these viruses are able to persist in the host's neural cells;once infected, individuals are at risk of recurrent clinicalmanifestations of infection which can be both physically andpsychologically distressing.

Herpes simplex viruses (HSV-1 and -2) are the causative agents of herpeslabialis and genital herpes. HSV infection is often characterised byextensive and debilitating lesions of the skin, mouth and/or genitals.Primary infections may be subclinical although tend to be more severethan infections in individuals previously exposed to the virus. Ocularinfection by HSV can lead to keratitis or cataracts thereby endangeringthe host's sight. Infection in the new-born, in immunocompromisedpatients or penetration of the infection into the central nervous systemcan prove fatal. In the US alone, 40 million individuals are infectedwith HSV-2, a number that is expected to increase to 60 million by 2007.Over 80% of individuals infected with HSV-2 are unaware they carry andspread the virus, and of those diagnosed less than 20% received oraltherapies. The net result is that less than 50/% of the infectedpopulation are treated. Likewise of the 530 million individualsworldwide who carry the HSV-1, 81% of the symptomatic population remainuntreated. No cure exists for HSV infection, and once infected,individuals carry the virus for life in a dormant state. Reactivation ofthe virus from latency occurs periodically and may be triggered bystress, environmental factors, and/or suppression of the host immunesystem. Currently, the use of nucleoside analogs such as valaciclovir(VALTREX®) and aciclovir (ZOVIRAX®) is the standard of care for managinggenital herpes virus outbreaks.

VZV is a herpes virus which causes chickenpox and shingles. Chickenpoxis the primary disease produced in a host without immunity, and in youngchildren is usually a mild illness characterised by a vesicular rash andfever. Shingles or zoster is the recurrent form of the disease whichoccurs in adults who were previously infected with VZV. The clinicalmanifestations of shingles are characterised by neuralgia and avesicular skin rash that is unilateral and dermatomal in distribution.Spread of inflammation may lead to paralysis or convulsions. Coma canoccur if the meninges become affected. VZV is of serious concern inpatients receiving immunosuppressive drugs for transplant purposes orfor treatment of malignant neoplasia and is a serious complication ofAIDS patients due to their impaired immune system.

In common with other herpes viruses, infection with CMV leads to alifelong association of virus and host. Congenital infection followinginfection of the mother during pregnancy may give rise to clinicaleffects such as death or gross disease (microcephaly,hepatosplenomegaly, jaundice, mental retardation), retinitis leading toblindness or, in less severe forms, failure to thrive, andsusceptibility to chest and ear infections. CMV infection in patientswho are immunocompromised for example as a result of malignancy,treatment with immunosuppressive drugs following transplantation orinfection with Human Immunodeficiency Virus, may give rise to retinitis,pneumonitis, gastrointestinal disorders and neurological diseases. CMVinfection is also associated with cardiovascular diseases and conditionsincluding restenosis and atheroslcerosis.

The main disease caused by EBV is acute or chronic infectiousmononucleosis (glandular fever). Examples of other EBV or EBV associateddiseases include lymphoproliferative disease which frequently occurs inpersons with congenital or acquired cellular immune deficiency, X-linkedlymphoproliferative disease which occurs namely in young boys,EBV-associated B-cell tumours, Hodgkin's disease, nasopharyngealcarcinoma, Burkitt lymphoma, non-Hodgkin lymphoma, thymomas and oralhairy leukoplakia. EBV infections have also been found in associationwith a variety of epithelial-cell-derived tumors of the upper and lowerrespiratory tracts including the lung. EBV infection has also beenassociated with other diseases and conditions including chronic fatiguesyndrome, multiple sclerosis and Alzheimer's disease.

HHV-6 has been shown to be a causative agent of infantum subitum inchildren and of kidney rejection and interstitial pneumonia in kidneyand bone marrow transplant patients, respectively, and may be associatedwith other diseases such as multiple sclerosis. There is also evidenceof repression of stem cell counts in bone marrow transplant patients.HHV-7 is of undetermined disease aetiology.

Hepatitis B virus (HBV) is a viral pathogen of world-wide majorimportance. The virus is aetiologically associated with primaryhepatocellular carcinoma and is thought to cause 80% of the world'sliver cancer. Clinical effects of infection with HBV range fromheadache, fever, malaise, nausea, vomiting, anorexia and abdominalpains. Replication of the virus is usually controlled by the immuneresponse, with a course of recovery lasting weeks or months in humans,but infection may be more severe leading to persistent chronic liverdisease outlined above.

BRIEF SUMMARY OF THE INVENTION

According to a first aspect of the invention there is provided a methodfor the prophylaxis or treatment of herpes viral infections in ananimal. The method comprises administering to the animal atherapeutically effective amount of a compound of formula (I):

wherein:

-   Z is CH or N;-   a is 1 or 2;-   b is 1, 2 or 3;-   c is 1, 2 or 3;-   each R¹ is independently selected from group consisting of    substituents of the formula    —(X)_(d)—(CH₂)_(e)—R⁵    wherein:-   d is 0 or 1;-   e is 0 to 6;-   X is selected from the group consisting of O, NR⁶ and S(O)_(f) where    f is 0, 1 or 2;-   R⁵ is selected from the group consisting of H, halo, C₁₋₆alkyl,    C₂₋₆alkenyl, C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl,    heteroaryl, hydroxyl, cyano, nitro, trihalomethyl, NR⁷R⁸, C₆H₄NR⁷R⁸,    C₆H₄(CH₂)NR⁷R⁸, C(O)R⁷, C(O)NR⁷R⁸, OC(O)R⁷, OC(O)NR⁷R⁸, CO₂R⁷,    OCO₂R⁷, SO₂R⁷, SO₂NR⁷R⁸, C(═NR⁷)NR⁷R⁸, NR⁷(C═NR⁷)NR⁷R⁸, NHC(O)R⁷ and    N(C₁₋₃alkyl)C(O)R⁷;-   each R² is independently selected from the group consisting of H,    cyano, halo, trihalomethyl, OC₁₋₆alkyl, C₁₋₆alkyl, C₂₋₆alkenyl,    C₂₋₆alkynyl, S(O)_(g)C₁₋₆alkyl where g is 0, 1 or 2,    NC₁₋₆alkyl(C₁₋₆alkyl), hydroxyl and nitro;-   each R⁴ is independently selected from the group consisting of    substituents of the formula    —(Y)_(d)—(CH₂)_(e)—R³    wherein:-   d is 0 or 1;-   e is 0 to 6;-   Y is O or S(O)_(f) where f is 0, 1 or 2;-   R³ is selected from the group consisting of H, halo, C₁₋₆alkyl,    C₂₋₆alkenyl, C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl,    heteroaryl, hydroxyl, cyano, nitro, trihalomethyl, phthalamido,    C₆H₄NR⁷R⁸, C₆H₄(CH₂)NR⁷R⁸, C(O)R⁷, C(O)NR⁷R⁸, OC(O)R⁷, OC(O)NR⁷R⁸,    CO₂R⁷, OCO₂R⁷, SO₂R⁷, SO₂NR⁷R⁸ and C(═NR⁷)NR⁷R⁸;-   R⁶ is selected from the group consisting of H, C₁₋₆alkyl,    C₂₋₆alkenyl, heteroaryl, cycloalkyl and heterocyclyl;-   R⁷ and R⁸ are each independently selected from the group consisting    of H, C₁₋₈alkyl, C₂₋₆alkenyl, SO₂C₁₋₆alkyl, (CH₂)_(m)-cycloalkyl,    (CH₂)_(m)-aryl, (CH₂)_(m)-heterocyclyl and (CH₂)_(m)-heteroaryl,    wherein m=0, 1 or 2,-   or R⁷ and R⁸ together with the nitrogen atom to which they are    bound, form a heterocyclyl group; and-   wherein any of said alkyl, alkenyl and alkynyl groups may be    optionally substituted with up to three substituents selected from    the group consisting of halo, hydroxyl, oxo, cyano, NR⁷R⁸,    C₁₋₆alkyl, OC₁₋₆alkyl, S(O)C₁₋₆alkyl, S(O)₂C₁₋₆alkyl and SO₂NR⁷R⁸;    and-   wherein any of said cycloalkyl, heterocyclyl, aryl and heteroaryl    groups may be optionally substituted with up to three substituents    selected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy,    C₁₋₆alkylsulfenyl, C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl, hydroxy,    oxo, mercapto, nitro, cyano, halo, C₁₋₆perfluoroalkyl, amino    optionally substituted by C₁₋₆alkyl, carbamoyl optionally    substituted by C₁₋₆alkyl, NR⁷R⁸, carboxy and aminosulfonyl    optionally substituted by C₁₋₆alkyl;-   wherein when (R¹)_(a) is at the 2′ position, (R¹)_(a) is not    NR⁶-aryl, NR⁶—C₆H₄NR⁷R⁸, NR⁶—C₆H₄—(CH₂)NR⁷R⁸, NR⁷R⁸ where R⁷ or R⁸    is (CH₂)_(m)-aryl and m is 0, or N-(aryl)[(C═NR⁷)NR⁷R⁸]; and-   wherein when R⁴ is at the C-7 position, R⁴ is not halo,    heterocyclyl, aryl, heteroaryl, phthalamido, C₆H₄NR⁷R⁸ or    C₆H₄(CH₂)NR⁷R⁸;    and pharmaceutically acceptable salts, solvates and physiologically    functional derivatives thereof.

The herpes viral infection may be herpes simplex virus 1, herpes simplexvirus 2, cytomegalovirus, Epstein Barr virus, varicella zoster virus,human herpes virus 6, human herpes virus 7, or human herpes virus 8.

According to a second aspect, the present invention provides a methodfor the prophylaxis or treatment of conditions or diseases associatedwith a herpes viral infection in an animal. The method comprisesadministering to the animal a therapeutically effective amount of thecompound of formula (I).

According to a third aspect, the present invention provides the use of acompound of formula (I), for the preparation of a medicament for theprophylaxis or treatment of a herpes viral infection in an animal. Thepresent invention also provides the use of a compound of formula (I),for the preparation of a medicament for the prophylaxis or treatment ofconditions or diseases associated with a herpes viral infection in ananimal.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “a compound of the invention” or “a compound of formula(I)” means a compound of formula (I) or a pharmaceutically acceptablesalt, solvate, or physiologically functional derivative thereof.

As used herein, the term “physiologically functional derivative” refersto any pharmaceutically acceptable derivative of a compound of thepresent invention, for example, an ester or an amide, which uponadministration to a mammal, such as a human, is capable of providing(directly or indirectly) a compound of formula (I) or an activemetabolite thereof. Such derivatives are clear to those skilled in theart, without undue experimentation, and with reference to the teachingof Burger's Medicinal Chemistry And Drug Discovery, 5^(th) Edition, Vol1: Principles And Practice.

As used herein, the terms “alkyl” and “alkylene” refer to straight orbranched hydrocarbon chains containing the specified number of carbonatoms. For example, C₁₋₆alkyl means a straight or branched alkylcontaining at least 1, and at most 6, carbon atoms. Examples of “alkyl”as used herein include, but are not limited to, methyl, ethyl, n-propyl,n-butyl, n-pentyl, isobutyl, and isopropyl. Examples of “alkylene” asused herein include, but are not limited to, methylene, ethylene,propylene and butylene. The alkyl groups may be optionally substitutedwith up to three substituents selected from the group consisting ofhalogen, hydroxyl, oxo, cyano, NR⁷R⁸, C₁₋₆alkyl, OC₁₋₆alkyl,S(O)C₁₋₆alkyl, S(O)₂C₁₋₆alkyl and SO₂NR⁷R⁸.

As used herein, the term “alkenyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms andcontaining at least one double bond. For example, C₂₋₆alkenyl means astraight or branched alkenyl containing at least 2, and at most 6,carbon atoms and containing at least one double bond. Examples of“alkenyl” as used herein include, but are not limited to ethenyl andpropenyl. The alkenyl groups may be optionally substituted with up tothree substituents selected from the group consisting of halogen,hydroxyl, oxo, cyano, NR⁷R⁸, C₁₋₆alkyl, OC₁₋₆alkyl, S(O)C₁₋₆alkyl,S(O)₂C₁₋₆alkyl and SO₂NR⁷R⁸.

As used herein, the term “alkynyl” refers to straight or branchedhydrocarbon chains containing the specified number of carbon atoms andcontaining at least one triple bond. For example, C₂₋₆alkynyl means astraight or branched alkynyl containing at least 2, and at most 6,carbon atoms and containing at least one triple bond. Examples of“alkynyl” as used herein include, but are not limited to, ethynyl andpropynyl. The alkynyl groups may be optionally substituted with up tothree substituents selected from the group consisting of halogen,hydroxyl, oxo, cyano, NR⁷R⁸, C₁₋₆alkyl, OC₁₋₆alkyl, S(O)C₁₋₆alkyl,S(O)₂C₁₋₆alkyl and SO₂NR⁷R⁸.

As used herein, the term “cycloalkyl” refers to a non-aromatichydrocarbon ring having from three to twelve carbon atoms. Thecycloalkyl ring may optionally contain up to three carbon-carbon doublebonds. “Cycloalkyl” includes by way of example cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The cycloalkyl ringmay be optionally substituted with substituents selected from a groupconsisting of C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylsulfenyl,C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl, hydroxy, oxo, mercapto, nitro,cyano, halogen, C₁₋₆perfluoroalkyl, amino optionally substituted byC₁₋₆alkyl, carbamoyl optionally substituted by C₁₋₆alkyl, NR⁷R⁸,carboxy, aminosulfonyl optionally substituted by C₁₋₆alkyl.

As used herein, the terms “heterocycle”, “heterocyclyl” and“heterocyclic” refer to a monocyclic five to seven membered non-aromatichydrocarbon ring or to a fused bicyclic non-aromatic hydrocarbon ringsystem comprising two of such monocyclic five to seven memberednon-aromatic hydrocarbon rings. The ring or rings contain at least oneheteroatom selected from O, S, or N where N-oxides, sulfur oxides andsulfur dioxides are permissible heteroatom substitutions. Theheterocycle ring system may optionally contain up to threecarbon-carbon, or carbon-nitrogen, double bonds. The heterocycle ringsystem may optionally be fused to one or more benzene rings. Examples ofheterocycles include, but are not limited to, tetrahydrofuran,dihydropyran, tetrahydropyran, pyran, oxetane, thietane, 1,4-dioxane,1,3-dioxane, 1,3-dioxalane, piperidine, tetrahydropyrimidine,pyrrolidine, morpholine, thiomorpholine, thiazolidine, oxazolidine,tetrahydrothiopyran, tetrahydrothiophene, and the like. Preferredheterocycles include morpholine, piperidine, and pyrrolidine. Theheterocycle ring system may be optionally substituted with substituentsselected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkylsulfenyl, C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl, hydroxy, oxo,mercapto, nitro, cyano, halogen, C₁₋₆perfluoroalkyl, amino optionallysubstituted by C₁₋₆alkyl, carbamoyl optionally substituted by C₁₋₆alkyl,NR⁷R⁸, carboxy and aminosulfonyl optionally substituted by C₁₋₆alkyl.

As used herein, the term “aryl” refers to an optionally substitutedphenyl or naphthyl ring. The aryl rings may be optionally substitutedwith substituents selected from the group consisting of C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkylsulfenyl, C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl,hydroxy, oxo, mercapto, nitro, cyano, halogen, C₁₋₆perfluoroalkyl, aminooptionally substituted by C₁₋₆alkyl, carbamoyl optionally substituted byC₁₋₆alkyl, NR⁷R⁸, carboxy, and aminosulfonyl optionally substituted byC₁₋₆alkyl.

As used herein, the term “heteroaryl” refers to a monocyclic five toseven membered aromatic ring, or to a fused bicyclic aromatic ringsystem comprising two of such monocyclic five to seven membered aromaticrings. These heteroaryl rings contain one or more nitrogen, sulfur, oroxygen heteroatoms, where N-oxides and sulfur oxides and dioxides arepermissible heteroatom substitutions. Examples of “heteroaryl” as usedherein include furan, thiophene, pyrrole, imidazole, pyrazole, triazole,tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole,isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline,isoquinoline, benzofuran, benzothiophene, indole, and indazole.Preferred heteroaryl groups include imidazole, pyridine and thiophene.The rings are optionally substituted with substituents selected from thegroup consisting of C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylsulfenyl,C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl, hydroxy, oxo, mercapto, nitro,cyano, halogen, C₁₋₆perfluoroalkyl, amino optionally substituted byC₁₋₆alkyl, carbamoyl optionally substituted by C₁₋₆alkyl, NR⁷R⁸, carboxyand aminosulfonyl optionally substituted by C₁₋₆alkyl.

As used herein, the term “alkoxy” refers to the group R_(a)O—, whereR_(a) is alkyl as defined above.

As used herein, the term “alkylsulfenyl” refers to the group R_(a)S—,where R_(a) is alkyl as defined above.

As used herein, the term “alkylsulfinyl” refers to the group R_(a)S(O)—,where R_(a) is alkyl as defined above.

As used herein, the term “alkylsulfonyl” refers to the group R_(a)SO₂—,where R_(a) is alkyl as defined above.

As used herein, the terms “halogen” or “halo” refer to the elementsfluorine, chlorine, bromine and iodine. Preferred halogens includefluorine, chlorine and bromine.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s)which occur and events that do not occur.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

As used herein, the terms “contain” or “containing” can refer to in-linesubstitutions at any position along the above-defined alkyl, alkenyl,alkynyl or cycloalkyl substituents with one or more of any of O, S, SO,SO₂, N, or N-alkyl, including, for example, —CH₂—O—CH₂—, —CH₂—SO₂—CH₂—,—CH₂—NH—CH₂— and so forth.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I) or a salt thereof) and a solvent. Such solvents for thepurpose of the invention may not interfere with the biological activityof the solute. Examples of suitable solvents include water, methanol,ethanol and acetic acid. Preferably the solvent used is apharmaceutically acceptable solvent. Examples of suitablepharmaceutically acceptable solvents include water, ethanol and aceticacid. Most preferably the solvent used is water.

Certain compounds of formula (I) may exist in stereoisomeric forms (e.g.they may contain one or more asymmetric carbon atoms or may exhibitcis-trans isomerism). The individual stereoisomers (enantiomers anddiastereomers) and mixtures of these are included within the scope ofthe present invention. The present invention also covers the individualisomers of the compounds represented by formula (I) as mixtures withisomers thereof in which one or more chiral centres are inverted.Likewise, it is understood that compounds of formula (I) may exist intautomeric forms other than that shown in the formula and these are alsoincluded within the scope of the present invention.

Compounds of formula (I):

include those compounds defined wherein R¹ contains an aryl,heterocyclic or heteroaryl moiety. In one embodiment, the compounds ofthe present invention include those compounds defined wherein R¹contains a heterocyclic or heteroaryl moiety.

Another class of compounds of formula (I) include those compoundsdefined wherein R¹ does not contain an aryl, heterocyclic or heteroarylmoiety. Another class of compounds of formula (I) include those definedwherein R¹ does not contain a heterocyclic or heteroaryl moiety but maycontain an aryl moiety.

Another class of compounds of formula (I) includes those compoundsdefined wherein at least one R⁴ group contains an aryl, heterocyclic orheteroaryl moiety. Another class of compounds of formula (I) includethose defined wherein R⁴ does not contain a heterocyclic or heteroarylmoiety but may contain an aryl moiety.

In one preferred class of compounds of formula (I), Z is CH. In anotherpreferred class of compounds of formula (I), Z is N.

In one preferred embodiment a is 1. In another preferred embodiment, ais 1 and R¹ is located in the 2′ position of the pyridine (i.e., when Zis CH) or pyrimidine (i.e., when Z is N) ring.

R¹ is —X_(d)—(CH₂)_(e)—R⁵. In one preferred embodiment R¹ is definedwhere d is 1. In one preferred embodiment of R¹, X is NR⁶. When X isNR⁶, R⁶ is preferably selected from the group consisting of H,C₁₋₆alkyl, cycloalkyl, heterocyclyl and heteroaryl.

In one embodiment e is 0-3. In one preferred embodiment, R¹ is definedwhere e is 0.

Examples of preferred embodiments include those compounds of formula (I)where R¹ is —NR⁶—(CH₂)_(e)—R⁵. In one embodiment of such preferredcompounds R⁶ is H or C₁₋₆alkyl, and R⁵ is selected from the groupconsisting of H, C₁₋₆alkyl, hydroxyl, NR⁷R⁸, cycloalkyl, heterocyclyl,and heteroaryl. In one preferred embodiment, R⁵ is selected from thegroup consisting of H, C₁₋₆alkyl, cycloalkyl, heterocyclyl andheteroaryl.

More particularly, preferred compounds of formula (I) include thosedefined where R¹ is selected from the group consisting of —NH₂,—NH(C₁₋₆alkyl), —NH(C₁₋₆alkyl)-OH, —NH(C₁₋₆alkyl)-NH₂, —NH(C₁₋₁-alkyl)-CF₃, —NH-heteroaryl, —NH(C₁₋₆alkyl)-heteroaryl,—NH(C₁₋₆alkyl)-aryl, —NH(C₁₋₆alkyl)-aryl(C₁₋₆alkoxy) and—NC₁₋₆alkyl(C₁₋₆alkyl).

Particular examples of preferred compounds of formula (I) include thosecompounds defined where R¹ is selected from the group consisting of—NH₂, —NH(CH₂)_(e)CH₃, —NH(CH₂)_(e)CH(CH₃)₂, —NH(CH₂)_(e)OH,—NH(CH₂)_(e)NH₂, —NH(CH₂)_(e)CF₃,

In one preferred embodiment, the compounds of formula (I) are definedwherein when (R¹)_(a) is located at the 2′ position of the pyridine orpyrimidine ring, (R¹)_(a) is not NR⁶-aryl, NR⁶—C₆H₄NR⁷R⁸,NR⁶—C₆H₄—(CH₂)NR⁷R⁸, NR⁷R⁸ where R⁷ or R⁸ is (CH₂)_(m)-aryl and m is O,or N-(aryl)[(C═NR⁷)NR⁷R⁸].

In one preferred embodiment of the present invention, the compounds offormula (I) are defined where b is 1 or 2. In another preferredembodiment b is 1.

R² is preferably selected from the group consisting of H, cyano, halo,trihalomethyl, C₁₋₆alkyl, OC₁₋₆alkyl, S(O)_(g)—C₁₋₆alkyl where g is 0, 1or 2, N—C₁₋₆alkyl(C₁₋₆alkyl), hydroxyl and nitro. More preferably, R² isselected from the group consisting of halo (e.g., fluoro or chloro),cyano, C₁₋₆alkyl (e.g., methyl), OC₁₋₆alkyl (O-methyl, O-isobutyl, andO—CH₂cyclopropyl), N—C₁₋₃alkyl(C₁₋₃alkyl) (e.g., methylamine,dimethylamine), and hydroxyl. In one preferred embodiment R² is fluoro.

In one preferred embodiment of the present invention, the compounds offormula (I) are defined where c is 1 or 2. In another preferredembodiment c is 1. In one preferred embodiment c is 1 and R⁴ is in the 5position. In one embodiment, the C-7 position of the pyrazolopyridinering is unsubstituted. In another embodiment, at least one R⁴ is in theC-7 position.

R⁴ is —(Y)_(d)—(CH₂)_(e)—R³. In one preferred embodiment, R⁴ is definedwhere d is 0. In another preferred embodiment R⁴ is defined where d is1.

In one preferred embodiment, R⁴ is defined where e is 0 to 3. In anotherpreferred embodiment e is 0 or 1.

Examples of preferred embodiments include those compounds of formula (I)where R⁴ is —(CH₂)_(e)—R³ where e is 0-3 and R³ is selected from thegroup consisting of H, halogen, trihalomethyl, C₁₋₆alkyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, hydroxyl, cyano, and C(O)NR⁷R⁸. In onepreferred embodiment, R³ is heterocyclyl.

When c is 1, 2 or 3, and one R⁴ is at the C-7 position, R⁴ at the C-7position is not a halo, a group containing an aryl ring attacheddirectly to the pyrazolopyridine ring or a group containing aheterocyclyl or heteroaryl ring attached directly to thepyrazolopyridine ring. More particularly, when c is 1, 2 or 3 and atleast one R⁴ is at the C-7 position, R⁴ at the C-7 position is not halo,heterocyclyl, aryl, heteroaryl, phthalamido, C₆H₄NR⁷R⁸ orC₆H₄(CH₂)NR⁷R⁸. In another embodiment, when R⁴ is at the C-7 position,R⁴ is not H.

R⁷ and R⁸ are preferably each independently selected from the groupconsisting of H, C₁₋₈alkyl, (CH₂)_(m)-cycloalkyl, (CH₂)_(m)-aryl,(CH₂)_(m)-heterocyclyl and (CH₂)_(m)-heteroaryl, where m is 0, 1 or 2.

Examples of preferred embodiments include those compounds of formula (I)where R⁴ is selected from the group consisting of H, F, Cl, Br,C₁₋₆alkyl, CF₃, CN, CH₂—NH-heterocyclyl, CH₂—OH, C(O)NH₂, andC(O)N(C₁₋₆alkyl)₂. More preferably, R⁴ is selected from the groupconsisting of H, F, Cl, Br, C₁₋₆alkyl, CF₃, CN, CH₂—NH-heterocyclyl andCH₂—OH.

It is to be understood that the present invention includes allcombinations of the particular and preferred groups defined hereinabove.

Preferred compounds of formula (I) include but are not limited to:

-   4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[2-(1H-imidazol-5-yl)ethyl]-2-pyridinamine;-   N-Butyl-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine;-   3-(4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinylamino)-1-propanol;-   N¹-4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinyl-1,3-propanediamine;-   4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-hexyl-2-pyridinamine;-   4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(4-methoxybenzyl)-2-pyridinamine;-   4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-pyridinylmethyl)-2-pyridinamine;-   4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-2-pyridinamine;-   2-(4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinylamino)-1-ethanol;-   N-Benzyl-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine;-   4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dimethyl-2-pyridinamine;-   N-Benzyl-6-fluoro-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine;-   4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-N-isopropyl-2-pyridinamine;-   3-(4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]-pyridin-3-yl]-2-pyridinylamino)-1-propanol;-   N-(3-Aminopropyl)-4-[6-bromo-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine;-   N-Butyl-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidin-amine;-   4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-propyl)-2-pyrimidinamine;-   4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   N-Benzyl-4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   N-Cyclopropyl-4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)-2-pyrimidinamine;-   3-(4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinylamino)-1-propanol;-   N-Cyclopropyl-4-[6-cyano-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   2-(4-Fluorophenyl)-3-(4-(2-(3-hydroxypropyl)amino)pyrimidinyl)-6-pyrazolo-[1,5-a]pyridinylcarboxamide;-   4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[2-(1H-imidazol-5-yl)ethyl]-2-pyrimidinamine;-   4-[2-(4-Fluorophenyl) pyrazolo[1,5-a]pyridin-3-yl]-N-(3-pyrid    inyl-methyl)-2-pyrimidinamine;-   4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-pyridinylmethyl)-2-pyrimidinamine;-   4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(4-pyridinyl-methyl)-2-pyrimidinamine;-   4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-pentyl-2-pyridinamine;-   N-Butyl-4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo-[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   N-{4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo-[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[3-(4-methylpiperazin-1-yl)propyl]amine;-   [3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-6-yl]methanol;-   N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-methylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   N-Cyclopentyl-4-[6-[(cyclopentylamino)methyl]-2-(4-fluorophenyl)    pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   4-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine;-   N-Cyclopentyl-4-[2-(4-fluorophenyl)-5-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   4-[5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine;-   1-[3-({4-[2-(4-Fluorophenyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinyl}amino)propyl]-2-pyrrolidinone;-   6-Fluoro-4-[2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridin-3-yl]-N-methyl-2-pyridinamine;-   4-[4-Fluoro-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridin-3-yl]-N,N-dimethyl-2-pyridinamine;-   N-Allyl-4-[2-(4-fluorophenyl)pyrazolo-[1,5-a]pyridin-3-yl]-2-pyridinamine;-   5-[6-Chloro-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyridinamine;-   3-({5-Bromo-4-[2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinyl}amino)-1-propanol;-   Methyl    3-(2-{[3-(acetyloxy)propyl]-amino}-4-pyridinyl)-2-(4-fluorophenyl)pyrazolo-[1,5-a]pyridine-6-carboxylate;-   3-[2-(Cyclopropylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carboxylic    acid;-   3-[2-(Cyclopropylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-N,N-dimethylpyrazolo-[1,5-a]pyridine-6-carboxamide;-   N-Cyclopropyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo-[1,5-a]pyridine-6-carboxamide;-   N-Cyclopentyl-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-6-phenyl-2-pyrimidinamine;-   2-(4-Fluorophenyl)-3-(4-pyrimidinyl)-pyrazolo[1,5-a]pyridine;-   2-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-pyrazolo[1,5-a]pyridine;-   2-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-pyrazolo[1,5-a]pyridine;-   2-(4-Fluorophenyl)-7-methyl-3-(4-pyrimidinyl)pyrazolo[1,5-a]pyridine;-   2-(4-Fluorophenyl)-7-methylthio-3-(4-pyrimidinyl)pyrazolo[1,5-a]pyridine;-   2-(4-Fluorophenyl)-7-methylsulfinyl-3-(4-pyrimidinyl)pyrazolo[1,5-a]-pyridine;-   7-(2-Fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylthio)    pyrimidinyl)-pyrazolo[1,5-a]pyridine;-   N-Butyl-4-[7-(2-fluoroethoxy)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   N-Benzyl-4-[7-(2-fluoroethoxy)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   2-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[-   1,5-a]pyridine;-   N-Butyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   N-Benzyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]-pyridin-3-yl]-2-pyrimidinamine;-   N-Cyclopropyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   N-Cyclohexyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   3-(4-[2-(4-Fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinylamino)-1-propanol;-   2-(4-Fluorophenyl)-3-(4-(2-methyloxy)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine;-   2-(4-Fluorophenyl)-3-(4-(2-phenyloxy)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine;-   2-(4-Fluorophenyl)-3-(4-(2-(2,2,2-trifluoroethoxy))pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine;-   2-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(ethylsulfinyl)-pyrazolo[1,5-a]pyridine;-   2-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-7-(ethylthio)-pyrazolo[1,5-a]pyridine;-   7-(2-Fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)-pyrimidinyl)-pyrazolo[1,5-a]pyridine;-   2-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)-pyrazolo[1,5-a]pyridine;-   2-(4-Fluorophenyl)-3-(4-pyridyl)-pyrazolo[1,5-a]pyridine;-   2-(4-Fluorophenyl)-7-methyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine;-   2-(4-Fluorophenyl)-7-methoxy-3-(4-pyridinyl)pyrazolo[1,5-a]-pyridine;-   2-(4-Fluorophenyl)-3-(2-fluoro-4-pyridinyl)-7-methoxypyrazolo[1,5-a]pyridine;-   N-Butyl-4-[2-(4-fluorophenyl)-7-methoxypyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine;-   N-{4-[5-Chloro-7-(ethylsulfanyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine;-   Ethyl    3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylate;-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylic    acid;-   3-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxamide;-   N-Butyl-4-[7-butyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   N-Butyl-4-[2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   N-Butyl-4-[2-(4-fluorophenyl)-7-octylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   N-Cyclopropyl-4-[7-ethyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine;-   Dimethyl    2-(4-fluorophenyl)-3-(4-(2-cyclopropylamino)pyrimidinyl)-7-pyrazolo[1,5-a]pyridinylcarboxamide;-   N-Cyclopentyl-4-[2-(4-fluorophenyl)-5-morpholin-4-ylpyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine;-   N¹-{4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N³,N³-dimethylpropane-1,3-diamine;-   3-(2-Butoxypyridin-4-yl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine;-   N-Cyclopentyl-4-[2-(2,4-dimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine;-   5-Bromo-4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentylpyrimidin-2-amine;-   N-Cyclopentyl-6-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-4-amine;-   N-Cyclopropyl-4-[2-(4-methoxyphenyl)-6-(trifluoromethyl)    pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine;-   N-Cyclopropyl-4-[2-(methoxyphenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine;-   Ethyl    3-[2-(cyclopropylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)-pyrazolo[1,5-a]pyridine-6-carboxylate;-   3-[2-(Cyclopropylamino)pyrimidin-4-yl]-N-(2-methoxyethyl)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-6-carboxamide;-   4-{5-Chloro-2-[4-(cyclopropyl    methoxy)phenyl]pyrazolo[1,5-a]pyridin-3-yl}-N-cyclopropyl-2-pyrimidinamine;-   4-[7-Butoxy-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine;-   4-[5-Chloro-2-(3-chlorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine;    and-   N-cyclopentyl-6-[2-(4-fluorophenyl)-7-(methylthio)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-4-amine.

It will be appreciated by those skilled in the art that the compounds ofthe present invention may also be utilized in the form of apharmaceutically acceptable salt, solvate or phsiologically functionalderivative thereof. The pharmaceutically acceptable salts of thecompounds of formula (I) include conventional salts formed frompharmaceutically acceptable inorganic or organic acids or bases as wellas quaternary ammonium salts. More specific examples of suitable acidsalts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric,perchloric, fumaric, acetic, propionic, succinic, glycolic, formic,lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic,methanesulfonic, naphthalene-2-sulfonic, benzenesulfonichydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like. Otheracids such as oxalic, while not in themselves pharmaceuticallyacceptable, may be useful in the preparation of salts useful asintermediates in obtaining the compounds of the invention and theirpharmaceutically acceptable salts. More specific examples of suitablebasic salts include sodium, lithium, potassium, magnesium, aluminium,calcium, zinc, N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methylglucamine and procaine salts.

The present invention provides compounds of formula (I) for use inmedical therapy, e.g. in the treatment or prophylaxis, includingsuppression of recurrence of symptoms, of a viral disease in an animal,e.g. a mammal such as a human. The compounds of formula (I) areespecially useful for the treatment or prophylaxis of viral diseasessuch as herpes viral infections. Herpes viral infections include, forexample, herpes simplex virus 1 (HSV-1), herpes simplex virus 2 (HSV-2),cytomegalovirus (CMV), Epstein Barr virus (EBV), varicella zoster virus(VZV), human herpes virus 6 (HHV-6), human herpes virus 7 (HHV-7), andhuman herpes virus 8 (HHV-8). The compounds of the invention are usefulin the treatment or prophylaxis of the symptoms or effects of herpesvirus infections.

The compounds of the invention are useful in the treatment orprophylaxis of conditions or diseases associated with herpes virusinfections, particularly conditions or diseases associated with latentherpes virus infection in an animal, e.g., a mammal such as a human. Byconditions or diseases associated with herpes viral infections is meanta condition or disease, excluding the viral infection per se, whichresults from the presence of the viral infection, such as chronicfatigue syndrome, which is associated with EBV infection, multiplesclerosis (MS) which has been associated with herpes viral infectionssuch as EBV and HHV-6. Other examples of conditions or diseases that areassociated with herpes virus infection include those described in thebackground section above.

In addition to those conditions and diseases, the compounds of thepresent invention may also be used for the treatment or prophylaxis ofcardiovascular diseases and conditions associated with herpes virusinfections, in particular atherosclerosis, coronary artery disease andrestenosis and specifically restenosis following angioplasty (RFA).Restenosis is the narrowing of the blood vessels which can occur afterinjury to the vessel wall, for example injury caused by balloonangioplasty or other surgical and/or diagnostic techniques, and ischaracterized by excessive proliferation of smooth muscle cells in thewalls of the blood vessel treated. It is thought that in many patientssuffering from RFA, viral infection, particularly by CMV and/or HHV-6 ofthe patient plays a pivotal role in the proliferation of the smoothmuscle cells in the coronary vessel treated. Restenosis can occurfollowing a number of surgical and/or diagnostic techniques, forexample, transplant surgery, vein grafting, coronary by-pass graftingand, most commonly following angioplasty.

There is evidence from work done both in vitro and in vivo, indicatingthat restenosis is a multifactorial process. Several cytokines andgrowth factors, acting in concert, stimulate the migration andproliferation of vascular smooth muscle cells (SMC) and production ofextracellular matrix material, which accumulate to occlude the bloodvessel. In addition growth suppressors act to inhibit the proliferationof SMC's and production of extracellular matrix material.

In addition, compounds of formula (I) may be useful in the treatment orprophylaxis of Hepatitis B and Hepatitis C viruses, human pappilomavirus (HPV) and human immunodeficiency virus (HIV).

The present invention provides a method for the treatment or prophylaxisof a viral infection in an animal such as a mammal (e.g., a human),particularly a herpes viral infection, which comprises administering tothe animal a therapeutically effective amount of the compound of formula(I).

As used herein, the term “prophylaxis” refers to the complete preventionof infection, the prevention of occurrence of symptoms in an infectedsubject, the prevention of recurrence of symptoms in an infectedsubject, or a decrease in severity or frequency of outward symptoms ofviral infection or disease in the subject.

As used herein, the term “treatment” refers to the partial or totalelimination of symptoms or decrease in severity of symptoms of viralinfection, condition or disease in the subject, or the elimination ordecrease of viral presence in the subject.

As used herein, the term “therapeutically effective amount” means anamount of a compound of formula (I) which is sufficient, in the subjectto which it is administered, to treat or prevent the stated disease,condition or infection. For example, a therapeutically effective amountof a compound of formula (I) for the treatment of a herpes virusinfection is an amount sufficient to treat or prevent the herpes virusinfection in the subject.

The present invention also provides a method for the treatment orprophylaxis of conditions or diseases associated with herpes viralinfections in an animal such as a mammal (e.g., a human), whichcomprises administering to the animal a therapeutically effective amountof the compound of formula (I). In one embodiment, the present inventionprovides a method for the treatment or prophylaxis of chronic fatiguesyndrome and multiple sclerosis in an animal such as a mammal (e.g., ahuman), which comprises administering to the animal a therapeuticallyeffective amount of a compound of formula (I). The foregoing method isparticularly useful for the treatment or prophylaxis of chronic fatiguesyndrome and multiple sclerosis associated with latent infection with aherpes virus.

In another embodiment, the present invention provides a method for thetreatment or prophylaxis of a cardiovascular condition such asatherosclerosis, coronary artery disease or restenosis (particularlyrestenosis following surgery such as angioplasty), which comprisesadministering to the animal a therapeutically effective antiviral amountof the compound of formula (I).

The present invention further provides a method for the treatment orprophylaxis of hepatitis B or hepatitis C viruses in an animal such as amammal (e.g., a human), which comprises administering to the animal atherapeutically effective amount of the compound of formula (I).

The present invention further provides a method for the treatment orprophylaxis of human papilloma virus in an animal such as a mammal(e.g., a human), which comprises administering to the animal atherapeutically effective amount of the compound of formula (I).

The present invention further provides a method for the treatment orprophylaxis of HIV in an animal such as a mammal (e.g., a human), whichcomprises administering to the animal a therapeutically effective amountof the compound of formula (I).

The present invention also provides the use of the compound of formula(I) in the preparation of a medicament for the treatment or prophylaxisof a viral infection in an animal such as a mammal (e.g., a human),particularly a herpes viral infection; the use of the compound offormula (I) in the preparation of a medicament for the treatment ofconditions or diseases associated with a herpes viral infection; and theuse of the compound of formula (I) in the preparation of a medicamentfor the treatment or prophylaxis of hepatitis B or hepatitis C viruses,human papilloma virus and HIV. In particular, the present invention alsoprovides the use of a compound of formula (I) in the preparation of amedicament for the treatment or prophylaxis of chronic fatigue syndromeor multiple sclerosis. In one embodiment, the present invention providesthe use of a compound of formula (I) in the preparation of a medicamentfor the treatment or prophylaxis of cardiovascular disease, such asrestenosis and atherosclerosis.

The compounds of formula (I) are conveniently administered in the formof pharmaceutical compositions. Such compositions may conveniently bepresented for use in any conventional manner in admixture with one ormore physiologically acceptable carriers or diluents.

While it is possible that compounds of the present invention may betherapeutically administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation orcomposition for convenient administration. Such compositions mayconveniently be presented for use in conventional manner in admixturewith one or more pharmaceutically acceptable carriers or diluents. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not deleterious to therecipient thereof.

Accordingly, the present invention further provides for a pharmaceuticalcomposition or formulation comprising a compound of formula (I) with oneor more pharmaceutically acceptable carriers or diluents therefore and,optionally, other therapeutic and/or prophylactic ingredients.

The formulations include those suitable for oral, parenteral (includingsubcutaneous e.g. by injection or by depot tablet, intradermal,intrathecal, intramuscular e.g. by depot and intravenous), rectal andtopical (including dermal, buccal and sublingual) administrationalthough the most suitable route may depend upon for example thecondition, age, and disorder of the recipient as well as the viralinfection or disease being treated. The formulations may conveniently bepresented in unit dosage form and may be prepared by any of the methodswell known in the art of pharmacy. All methods include the step ofbringing into association the compound(s) (“active ingredient”) with thecarrier or diluent and optionally one or more accessory ingredients. Ingeneral the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers ordiluents or finely divided solid carriers or diluents or both and then,if necessary, shaping the product into the desired formulation.

Formulations suitable for oral administration may be presented asdiscrete units such as capsules, cachets or tablets (e.g. chewabletablets in particular for paediatric administration) each containing apredetermined amount of the active ingredient; as a powder or granules;as a solution or a suspension in an aqueous liquid or a non-aqueousliquid; or as an oil-in-water liquid emulsion or a water-in-oil liquidemulsion. The active ingredient may also be presented as a bolus,electuary or paste. A tablet may be made by compression or moulding,optionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as a powder or granules,optionally mixed with other conventional excipients such as bindingagents, (for example, syrup, acacia, gelatin, sorbitol, tragacanth,mucilage of starch or polyvinylpyrrolidone), fillers (for example,lactose, sugar, microcrystalline cellulose, maize-starch, calciumphosphate or sorbitol), lubricants (for example, magnesium stearate,stearic acid, talc, polyethylene glycol or silica), disintegrants (forexample, potato starch or sodium starch glycollate) or wetting agents,such as sodium lauryl sulfate. Moulded tablets may be made by mouldingin a suitable machine a mixture of the powdered compound moistened withan inert liquid diluent. The tablets may optionally be coated or scoredand may be formulated so as to provide slow or controlled release of theactive ingredient therein. The tablets may be coated according tomethods well-known in the art.

Alternatively, the compounds of the present invention may beincorporated into oral liquid preparations such as aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, for example.Moreover, formulations containing these compounds may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may contain conventional additives such assuspending agents such as sorbitol syrup, methyl cellulose,glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats;emulsifying agents such as lecithin, sorbitan mono-oleate or acacia;non-aqueous vehicles (which may include edible oils) such as almond oil,fractionated coconut oil, oily esters, propylene glycol or ethylalcohol; and preservatives such as methyl or propyl p-hydroxybenzoatesor sorbic acid. Such preparations may also be formulated assuppositories, e.g., containing conventional suppository bases such ascocoa butter or other glycerides.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations may be presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilised) condition requiring only the addition of asterile liquid carrier, for example, water-for-injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions may beprepared from sterile powders, granules and tablets of the kindpreviously described. Formulations for rectal administration may bepresented as a suppository with the usual carriers such as cocoa butter,hard fat or polyethylene glycol. Formulations for topical administrationin the mouth, for example buccally or sublingually, include lozengescomprising the active ingredient in a flavoured base such as sucrose andacacia or tragacanth, and pastilles comprising the active ingredient ina base such as gelatin and glycerin or sucrose and acacia.

The compounds may also be formulated as depot preparations. Such longacting formulations may be administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection. Thus,for example, the compounds may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question, for example thosesuitable for oral administration may include flavouring agents.

It will be appreciated that the amount of a compound of the inventionrequired for use in treatment will vary with the nature of the conditionbeing treated and the age and the condition of the patient and will beultimately at the discretion of the attendant physician or veterinarian.In general, however, doses employed for adult human treatment willtypically be in the range of 0.02-5000 mg per day, preferably 100-1500mg per day. The desired dose may conveniently be presented in a singledose or as divided doses administered at appropriate intervals, forexample as two, three, four or more sub-doses per day. The formulationsaccording to the invention may contain between 0.1-99% of the activeingredient, conveniently from 30-95% for tablets and capsules and 3-50%for liquid preparations.

The compound of formula (I) for use in the instant invention may be usedin combination with other therapeutic agents for example, non-nucleotidereverse transcriptase inhibitors, nucleoside reverse transcriptaseinhibitors, protease inhibitors and/or other antiviral agents. Theinvention thus provides in a further aspect the use of a combinationcomprising a compound of formula (I) with a further therapeutic agent inthe treatment of viral infections. Particular antiviral agents which maybe combined with the compounds of the present invention includeaciclovir, valaciclovir, famcyclovir, gancyclovir, docosanol, miribavir,amprenavir, lamivudine, zidovudine, and abacavir. Preferred antiviralagents for combining with the compounds of the present invention includeaciclovir and valaciclovir. Thus the present invention provides in afurther aspect, a combination comprising a compound of formula (I) andan antiviral agent selected from the group consisting of aciclovir orvalaciclovir; the use of such combination in the treatment of viralinfections and the preparation of a medicament for the treatment ofviral infections, and a method of treating viral infections comprisingadministering a compound of formula (I) and an antiviral agent selectedfrom the group consisting of aciclovir and valaciclovir.

When the compound of formula (I) is used in combination with othertherapeutic agents, the compounds may be administered eithersequentially or simultaneously by any convenient route.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above optionallytogether with a pharmaceutically acceptable carrier or diluent comprisea further aspect of the invention. The individual components of suchcombinations may be administered either sequentially or simultaneouslyin separate or combined pharmaceutical formulations.

When combined in the same formulation it will be appreciated that thetwo compounds must be stable and compatible with each other and theother components of the formulation and may be formulated foradministration. When formulated separately they may be provided in anyconvenient formulation, in such a manner as are known for such compoundsin the art.

When a compound of formula (I) is used in combination with a secondtherapeutic agent active against the viral infection, the dose of eachcompound may differ from that when the compound is used alone.Appropriate doses will be readily appreciated by those skilled in theart.

The compounds employed in this present invention may be made by avariety of methods, utilizing standard chemistry. Any previously definedvariable will continue to have the previously defined meaning unlessotherwise indicated. Illustrative general synthetic methods are set outbelow and then specific compounds of the invention are prepared in theworking Examples.

For example, a general method (A) for preparing the compounds of Formula(I) comprises the reaction of a compound of Formula (VII)

with a compound of Formula (VIII) or a compound of Formula (IX):

wherein Z is CH or N and Y is methyl or butyl.

This general method (A) can be conveniently performed by mixing the twocompounds in an inert solvent, in the presence of a palladium catalyst,and optionally heating the mixture to about 100° C. Preferably thereaction is performed using an approximately equimolar mixture of (VII)and (VIII), or an approximately equimolar mixture of (VII) and (IX). Thepalladium catalyst is preferably present in the proportion of 1-5 mol %compared to (VII). Palladium catalysts which may be used include, butare not limited to, tetrakistriphenylphosphine palladium(0),bis(triphenylphosphine)palladium dichloride. When one of the reactantpartners is a compound of formula (IX), the reaction is moreconveniently carried out by adding a base in a proportion equivalent to,or greater than, that of (IX). Preferably the base is a trialkylamine orsodium hydrogen carbonate.

Another general method (B) for the preparation of the compounds of thisinvention is the reaction of a compound of Formula (VII) with a compoundof Formula (X) as summarized below to give compounds of Formula (I)where R¹ is hydrogen.

The type of reaction utilized in general method (B) is well documentedin the literature and is routinely referred to as a ‘Stille’ coupling(Stille, Angew. Chem. Int. Ed. Engl. 1986, 25, 508). This reaction isbrought about by mixing the two reactants in an inert solvent in thepresence of a catalytic quantity of a palladium species and heating thereaction mixture. Conveniently the solvent is, for example, toluene,dioxane, tetrahydrofuran or dimethylformamide and the palladium catalystis a palladium(0) species, or a convenient precursor thereof, forexample, tetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium dichloride. For example, when R⁴ ishydrogen, the reaction is most conveniently performed by mixing the tworeactants, in an approximate equimolar ratio, in toluene, adding anamount of tetrakis(triphenylphosphine)palladium(0) equal to about 5 mol% of that of (VII), and heating the mixture at about 100-120° C. untilthe reaction is judged complete by the disappearance of either (VII) or(X). Typically this reaction requires between 12 and 48 hours to proceedto completion. The product can be conveniently isolated using procedurestypical for this Stille coupling procedure.

One skilled in the art will recognize that a similar reaction,illustrated below in general method (C) can be used to prepare compoundsof the invention using boron containing reactants such as (XII).

The use of boronic acids, or esters, in such a coupling reaction istypically referred to as a ‘Suzuki’ coupling reaction (Suzuki, A. et al.Synth. Commun. 1981, 11, 513). Said reaction is conveniently broughtabout by mixing the two reactants, in an inert solvent, in the presenceof a catalytic quantity of a palladium species and a base, and heatingthe reaction mixture. Conveniently the solvent is, for example, toluene,dioxane, tetrahydrofuran or dimethylformamide and the palladium catalystis a palladium(0) species, or a convenient precursor thereof, forexample, tetrakis(triphenylphosphine)palladium(0) orbis(triphenylphosphine)palladium dichloride, and the base is sodiumbicarbonate or a trialkyl amine such as triethyl amine.

Boron containing compounds such as (XII) and tin containing compoundssuch as (X) are either commercially available or can be prepared usingmethods known to one skilled in the art (Stille, Angew. Chem. Int. Ed.Engl. 1986, 25, 508; Snieckus, V. et al. J. Org. Chem. 1995, 60, 292-6).

Compounds of formula (VII) may be conveniently prepared from compoundsof Formula (XII) by a decarboxylation/bromination sequence as shownbelow.

This reaction can be achieved by treatment of a compound of formula(XII), dissolved in a suitable solvent, with a base followed by abrominating agent and stirring the mixture at, or about, 25° C. untilthe reaction is judged complete by the disappearance of (XII). Suitablesolvents include, but are not limited to, dimethylformamide,dimethylacetamide, dioxane and the like. Conveniently the base is sodiumhydrogen carbonate and the brominating agent can be, for example,N-bromosuccinimide. Alternatively, compounds of formula (VII) can beconveniently prepared by treatment of a compound of formula (XIII) witha brominating agent as summarized below.

This reaction can be easily carried out by dissolving the compound offormula (XIII) in an inert solvent and adding to the solution abrominating agent in sufficient quantity to effect complete reaction of(XIII). Preferably the solvent is dimethylformamide, dimethylacetamide,dioxane and the like and brominating agents include, but are not limitedto, bromine, N-bromosuccinimide, N-bromoacetamide and the like.

Compounds of formula (XIII) may be conveniently prepared by thedecarboxylation of a compound of formula (XII) as summarized below.

Said decarboxylation may be carried out by any one of a variety ofmethods described in the literature for similar decarboxylations. Forexample: heating a solution of a compound of formula (XII) in an inertsolvent, or conversion to a ‘Barton ester’ followed by treatment with aradical reductant, for example tributyltin hydride (Crich, D.Aldrichimica Acta, 1987, 20, 35).

Compounds of formula (XII) can be prepared most readily by simplehydrolysis of lower alkyl esters of formula (XIV). Esters such as (XIV)are commonly referred to as pyrazolo[1,5-a]pyridines (Hardy, C. R. Adv.Het. Chem. 1984, 36, 343) and may be prepared by a cycloadditionreaction between compounds of formula (XV) and acetylenes of formula(XVI), as summarized below.

Cycloaddition reactions such as these are commonly known as [3+2]dipolar cycloaddition reactions. Conveniently the reaction may becarried out by mixing the reactants (XV) and (XVI), in equimolaramounts, in an inert solvent and adding a suitable base. The mixture isthen stirred at between 20-100° C. until the reaction is judged completeby the disappearance of one of the reactants. Preferred solvents includebut are not limited to acetonitrile, dioxane, tetrahydrofuran,dimethylformamide and the like. Preferred bases include non-nucleophilicamines such as 1,8-diazabicyclo[5.4.0]undec-7-ene,1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane and thelike.

Esters such as those of Formula (XIV) can be conveniently hydrolyzed totheir corresponding carboxylic acids by standard hydrolysis conditionsemployed to effect similar hydrolysis reactions (Larock, ComprehensiveOrganic Transformations, 1989, 981). For example, treatment of asolution of a compound of formula (XIV) in a lower alcohol, for examplemethanol, with sodium hydroxide followed by heating the mixture for anappropriate time gives the compound of formula (XII).

Compounds of formula (XV) are aminated pyridine derivatives and areeither commercially available or can be conveniently prepared byreacting a suitable pyridine with an aminating reagent such asO-(mesitylsulfonyl)hydroxylamine, O-(diphenylphosphinyl)hydroxylamineand the like.

Acetylenic esters such as those of formula (XVI) are either knowncompounds or can be prepared by methods described in the literature.Preferred methods include the reaction of acetylenes such as those offormula (XVII) with a suitable base to generate an acetylenic anion andsubsequent reaction of the anion with an alkoxycarbonylating agent, assummarized below.

Preferably the acetylene (XVII) is dissolved in an inert solvent, suchas tetrahydrofuran, and the solution is cooled to about −75° C. A baseis added in sufficient quantity to effect deprotonation of the acetylene(XVII). The preferred bases include, but are not limited to,n-butyllithium, lithium diisopropylamide, sodiumbis(trimethylsilyl)amide and the like. To the reaction mixture is thenadded a reagent capable of reacting with an anion to introduce analkoxycarbonyl group. Preferred reagents include, but are not limitedto, methyl chloroformate, ethyl chloroformate, benzyl chloroformate andthe like. Arylalkynes such as (XVII) are either known compounds or canbe prepared by literature methods such as those described in, forexample, Negishi, E. J. Org. Chem. 1997, 62, 8957.

Compounds of formula (XIII) can also be prepared via a number of otherconvenient routes. Disubstituted acetylenes as represented by formula(XVIII) can be treated with an aminating agent, optionally in thepresence of a base, to give compounds of formula (XIII). The aminatingagent is, preferably, O-(mesitylsulfonyl)hydroxylamine and the base ispotassium carbonate.

Disubstituted acetylenes such as (XVIII) are readily prepared by apalladium catalyzed coupling reaction between aryl acetylenes and2-halopyridines using methods described in the literature (Yamanake etal, Chem. Pharm. Bull. 1988, 1890).

An alternative synthesis of compounds of formula (XIII) involvestreating a ketone of formula (XIX) with an aminating agent in a suitablesolvent and optionally heating the reaction. The aminating agent is,preferably, O-(mesitylsulfonyl)hydroxylamine and preferred solventsinclude chloroform, dichloromethane and the like.

Ketones such as those of formula (XIX) can be readily prepared usingprocedures described in the literature (Cassity, R. P.; Taylor, L. T.;Wolfe, J. F. J. Org. Chem. 1978, 2286).

A more preferred approach to compounds of formula (XIII) involves theconversion of ketones of formula (XIX) to oximes such as (XX) followedby treatment of said oximes with an aminating agent

Typically, oximes of formula (XX) are readily prepared by treatingketones of formula (XIX) with a source of hydroxylamine, in anappropriate solvent, and optionally in the presence of a base.Preferably the source of hydroxylamine is hydroxylamine hydrochlorideand the base is sodium carbonate, potassium carbonate, or an aqueoussolution of sodium hydroxide. Preferred solvents include lower alcohols,such as methanol and ethanol, or acetonitrile. The aminating agent is,preferably, O-(mesitylsulfonyl)hydroxylamine and preferred solventsinclude chloroform, dichloromethane and the like.

A still more preferred method for the preparation of compounds offormula (XIII) from oximes of formula (XX) involves the treatment of thesaid oximes with an acylating or sulfonylating agent in the presence ofa base to generate azirines of formula (XXI).

Azirines such as (XXI) can be rearranged to compounds of formula (XIII)by heating a solution of said azirine in a suitable solvent attemperatures of about 100-180° C. More preferably the rearrangement iscarried out in the presence of FeCl₂. In the presence of FeCl₂ therearrangement occurs at lower temperatures and in a higher yield.Typically the azirines (XXI) can be prepared by treatment of oximes offormula (XX) with acetic anhydride, trifluoroacetic anhydride,methanesulfonyl chloride, toluenesulfonyl chloride and the like in aninert solvent, for example, chloroform, dichloromethane or toluene.Preferred bases include, but are not limited to, triethylamine,diisopropylethylamine, pyridine and the like.

A general method (D) for the preparation of compounds of formula (V)comprises the reaction of a compound of formula (XXII) with a compoundof formula (XXIII).

-   -   wherein Q is alkyloxy, alkylthio or dialkylamino.

The general method (D) can be readily carried out by mixing a compoundof formula (XXII) with a compound of formula (XXIII) in a suitablesolvent, optionally in the presence of a base, and heating the reactionmixture to about 50-150° C. Typically the solvent is a lower alcoholsuch as methanol, ethanol, isopropanol and the like, and the base canbe, for example, a sodium alkoxide, potassium carbonate or an amine basesuch as triethylamine.

Compounds of formula (XXII) may be conveniently prepared by reacting acompound of formula (XXIV) with a dimethylformamide dialkylacetal, togive compounds of formula (XXII) wherein Q is Me₂N, or with a trialkylorthoformate or a dialkoxymethyl acetate, to give compounds of formula(XXII) wherein Q is an alkoxy group. Conveniently, a dimethylformamidedialkylacetal is dimethylformamide dimethyl acetal or dimethylformamidedi-tert-butyl acetal and the reaction carried out by mixing the compoundof formula (XXIV) with the dimethylformamide dialkylacetal andoptionally heating the reaction. Preferred trialkyl orthoformatesinclude trimethyl orthoformate and triethyl orthoformate. In a similarmanner, diethoxymethyl acetate can be employed to prepare compounds offormula (XXII) wherein Q is EtO—.

Compounds of formula (XXIV) can be prepared from compounds of formula(XIII) by an acylation procedure.

Typically the acylation is conveniently carried out by treating thecompounds of formula (XIII) with an acylating agent optionally in thepresence of an acid catalyst. The preferred acylating agent is aceticanhydride (“Ac₂O”) and a convenient acid is sulfuric acid.

Methods for the synthesis of compounds of formula (XIII) are describedabove.

Certain compounds of formula (V) may be conveniently prepared by aprocess which involves reacting a ketone of formula (XXV) with anN-aminopyridine derivative in the presence of an acid or a base.Typically the acid is p-toluenesulfonic acid and the base can bepotassium carbonate, sodium hydroxide, cesium carbonate, lithiumhydroxide, triethylamine, potassium tert-butoxide.

Compounds of formula (I) can also be converted to other compounds offormula (I). For example, reaction of a compound of formula (XXXVII)with a non-nucleophilic base, for example n-butyllithium, followed bytreatment with an electrophilic agent gives compounds of formula(XXXVIII), as summarized below.

Electrophiles which can be successfully used in this procedure include,but are not limited to: alkyl halides (E=methyl, benzyl etc.);N-bromosuccinimide (E=bromine); N-chlorosuccinimide (E=chlorine);N-iodosuccinimide (E=iodine); aldehydes (E=CH(OH)R); dimethylformamide(E=CHO); dimethyl disulfide (E=SMe); carbon dioxide (E=CO₂H);dimethylcarbamoyl chloride (E=C(O)NMe₂) and the like.

Compounds of formula (XXXVIII), wherein E is a halogen such as chloride(XXXVIII-A), or a sulfone, such as p-tolylsulfonyl, can be transformedinto compounds in which E is an ether group by treatment of said chloro,or p-tolylsulfonyl, derivative with alcohols as summarized below.

This transformation is most conveniently carried out by mixing thechloride of formula (XXXVIII-A) with an excess of the alcohol,optionally in the presence of an inert solvent, and heating the mixtureto about 100-150° C.

As another example, compounds of formula (I) wherein R¹ is a leavinggroup, for example a halogen such as chloride, or a sulfone such asmethanesulfonyl can be converted into compounds of formula (I) whereinR¹ is an ether or an amino group by treatment of said chloro, ormethanesulfonyl derivative with alcohols or amines. Thus, a particularlypreferred method for synthesising compounds of formula (V) wherein R¹ is—NH—(CH₂)_(e)—R⁵ is shown below.

A compound of formula (XXVI) is mixed at room temperature with a neatamine of general formula H₂N—(CH₂)_(e)—R₅. The mixture is then heatedwith an airgun until a homogenoeous melt is obtained. This usually takesabout 2 minutes. Upon cooling, water is added and the compound offormula (I) precipates out and may be separated by filtration.

Compounds of formula (XXVI) may be produced by the reaction of oxonewith compounds of formula (XXVII) as shown below.

Compounds of formula (XXVII) may be produced by reaction of a compoundof formula (VII) with a compound of formula (VIII) wherein Z is N, R¹ is—SMe and Y is butyl. The synthesis of a compound of formula (VIII)wherein Z is N, R¹ is —SMe and Y is butyl is described in the literature(Sandosham, J. and Undheim, K. Tetrahedron 1994, 50, 275; Majeed, A J.et al Tetrahedron 1989, 45, 993).

Compounds of formula (I), wherein R⁴ is hydrogen can be converted intocompounds wherein R⁴ is bromide or iodide and is attached to position 6.Said conversion is conveniently carried out by addition of a brominatingagent such as N-bromosuccinimide, or an iodinating agent such asN-iodosuccinimide, to a solution of a compound of formula (XXX) in anappropriate solvent. Preferred solvents include dimethylformamide,dichloromethane and the like.

Compounds of formula (I), wherein R⁴ is a bromide or iodide and isattached to position 6 or 7 can be converted to compounds with differentsubstitutions at position 6 or 7, respectively, by a variety of methods.For example, treatment of a compound of formula (XXXI), wherein R⁴ isbromide or iodide, under conditions well known in the art as Stillecoupling reactions or Suzuki coupling reactions leads to compoundswherein R⁴ is alkyl, alkenyl, alkynyl, cyano, or carboalkoxy.

Compounds of formula (XXXI-A) wherein R⁴ is a trifluoromethyl group(CF₃) can be converted into compounds wherein R⁴ is a carboxylic acidderivative. Preferably said transformation is carried out by treatmentof a compound of formula (XXXII) with a suitable base in an alcoholicsolvent and optionally heating the reaction to about 80° C. Preferablythe base is a sodium or potassium alkoxide such as sodium ethoxide andthe like and the preferred solvents include, but are not limited to,methanol, ethanol, propanol, isopropanol and the like. The resultingtrialkylorthoesters can be converted to lower alkyl esters by treatmentof said orthoesters in a suitable solvent with an acid in the presenceof water. Preferred acids include p-toluenesulfonic acid, hydrochloricacid and sulfuric acid and the preferred solvents include lower alcoholsand acetone. Lower alkyl esters such as those represented by formula(XXXIII) can be further converted into different compounds bytransformation of the ester group in a manner well known in the art.

Compounds of formula (I), wherein R¹, R² or R⁴ contains a hydroxyl groupcan be reacted to give compounds wherein the hydroxyl group is convertedto an ester, carbonate or carbamate group using procedures well known inthe literature (March J. Advanced Organic Chemistry).

Similarly, compounds of general formula (I), wherein R¹, R² or R⁴contains an amino group attached to the pyrazolopyridine ring throughanother functional group, can be reacted to give compounds wherein theamino group is converted to an amide, carbamate or urea group usingprocedures known in the literature (March J. Advanced OrganicChemistry).

Certain compounds of formula (I) wherein at least one R² group issubstituted on an ortho position of the phenyl ring may be prepared bythe reaction of a compound of formula (XXXIV) wherein Y is methyl orbutyl:

with a compound of formula (XXXV):

This reaction is essentially the reverse of the coupling reactiondescribed above between compounds of formula (VIII) and (IX). Thereaction conditions are analogous to those previously described for thecoupling reaction between compounds of formula (VIII) and (IX).

Compound (XXXIV) wherein Y is butyl may be prepared from a compound offormula (VII) using a strong base, butyl lithium and tri-n-butyl stannylchloride at low temperature (e.g. −78° C.) in an inert solvent such astetrahydrofuran (THF).

The following examples are intended for illustration only and are notintended to limit the scope of the invention in any way. Reagents arecommercially available or are prepared according to procedures in theliterature. Example numbers refer to those compounds listed in thetables above. ¹H and ¹³C NMR spectra were obtained on Varian Unity PlusNMR spectrophotometers at 300 or 400 MHz, and 75 or 100 MHzrespectively. ¹⁹F NMR were recorded at 282 MHz. Mass spectra wereobtained on Micromass Platform, or ZMD mass spectrometers from MicromassLtd. Altrincham, UK, using either Atmospheric Chemical Ionization (APCI)or Electrospray Ionization (ESI). Analytical thin layer chromatographywas used to verify the purity of some intermediates which could not beisolated or which were too unstable for full characterization, and tofollow the progress of reactions. Unless otherwise stated, this was doneusing silica gel (Merck Silica Gel 60 F254). Unless otherwise stated,column chromatography for the purification of some compounds, used MerckSilica gel 60 (230-400 mesh), and the stated solvent system underpressure. All compounds were characterized as their free-base formunless otherwise stated. On occasion the corresponding hydrochloridesalts were formed to generate solids where noted.

EXAMPLE 14-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[2-(1H-imidazol-5-yl)ethyl]-2-pyridinamine

a) 1-(4-Fluorophenyl)-2-trimethylsilylacetylene

4-Fluoroiodobenzene (112 mL, 0.97 mol) and triethylamine (176 mL, 1.26mol) are dissolved in dry THF (1.2 L) and nitrogen gas was bubbledthrough the solution for about 20 min. Copper (I) iodide (1.08 g, 5.7mmol) and bis(triphenyphosphine)-palladium dichloride (2.15 g, 3 mmol)are added and then trimethylsilylacetylene (178 mL, 1.3 mol) was addeddropwise over about 40 min with the temperature being maintained atabout 23° C. A large amount of precipitate forms (presumably Et₃NHCl)which necessitates mechanical stirring. Following complete addition ofthe trimethylsilylacetylene the mixture was allowed to stir at roomtemperature for about 18 hours. The mixture was filtered and the solidwashed with cyclohexane. The combined filtrates are concentrated underreduce pressure to give a brown oil. Application of this oil to a pad ofsilica gel followed by elution with cyclohexane gave a yellow solution.Removal of the solvent gave the title compound as a yellow oil; 182.8 g(95%).

b) Methyl 3-(4-fluorophenyl)propiolate

A solution of 1-(4-fluorophenyl)-2-trimethylsilylacetylene (64 g, 0.33mol) in dry diethyl ether (400 mL) was cooled to 0° C. under a nitrogenatmosphere. To this solution was added, dropwise over 45 minutes, asolution of tetrabutylammonium fluoride (1M in THF, 330 mL, 0.33 mol)via a dropping funnel maintaining the internal temperature below 2° C.The mixture was allowed to warm to room temperature over about 1 hour.Diethyl ether (300 mL) was added to the mixture and the organic solutionwas washed with water, saturated brine and then dried over anhydrousmagnesium sulfate. The magnesium sulfate was removed by filtration andthe filtrate was cooled to about −78° C. n-Butyl lithium (1.6M inhexanes, 450 mL, 0.72 mol) was added dropwise via a dropping funnel overabout 1 hour while the temperature was maintained below −66° C. Aftercomplete addition the mixture was stirred at −78° C. for about 1 hourand then a precooled solution of methyl chloroformate (110 mL, 1.4 mol)in dry diethyl ether (200 mL) was added in a continuous stream as fastas possible. The mixture was allowed to cool to −78° C. and then allowedto warm to room temperature over 1.5 hours. The organic reaction mixturewas washed with water and saturated brine and then dried over anhydrousmagnesium sulfate. The solvents are remove under reduced pressure andthe residue dried under reduced pressure to give the title compound as abrown solid, 36.5 g (61%). ¹H NMR (CDCl3) δ 7.58 (dd, 2H, J=9, 5.4 Hz),7.07 (t, 2H, J=8.5 Hz), 3.84 (s, 3H). MS (+ve ion electrospray) 178(30), (M⁺).

c) Methyl 2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylate

A stirred solution of methyl 3-(4-fluorophenyl)propiolate (8.02 g, 45mmol) and 1-aminopyridinium iodide (10 g, 45 mmol) in dry acetonitrile(150 mL) was cooled to about 0° C. A solution of1,8-diazabicycloundec-7-ene (13.7 g, 90 mmol) in dry acetonitrile (50mL) was added dropwise over 1 hour. The mixture was allowed to stir atroom temperature for about 18 hours. The reaction mixture was cooled inan ice bath for about 30 min. and the precipitate was collected byfiltration and washed with cold acetonitrile (10 mL). The solid wasdried under reduced pressure to give the title compound as a whitesolid, 8.48 g (70%). ¹H NMR (CDCl3) δ 8.50 (d, 1H, J=8.4 Hz), 8.18 (d,1H, J=8.8 Hz), 7.78 (m, 2H), 7.42 (t, 1H, J=8.4 Hz), 7.13 (t, 2H, J=8.8Hz), 6.97 (td, 1H, J=6.8, 1 Hz). MS (+ve ion electrospray) 271 (100),(MH⁺).

d) 2-(4-Fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylic Acid

A solution of methyl2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylate (5.0 g, 18.5mmol) in 2N aqueous sodium hydroxide (50 ml) and methanol (30 mL) washeated at reflux for about 3 hours. The mixture was filtered and thefiltrate was washed with diethyl ether (20 mL) and then concentratedunder reduced pressure to about half the original volume. Concentratedhydrochloric acid was added to adjust the pH to about 2 and theresulting solid was collected by filtration and washed with water anddried under vacuum to give the title compound as a white solid, 4.8 g(ca. 100%). ¹H NMR (d6 DMSO) δ 12.43 (s, 1h), 8.84 (d, 1H, J=6.9 Hz),8.14 (d, 1H, J=9 Hz), 7.82 (m, 2H), 7.57 (t, 1H, J=8.1 Hz), 7.28 (t, 2H,J=9 Hz), 7.15 (td, 1H, J=6.9, 1.2 Hz). MS (+ve ion electrospray) 257(100), (MH⁺).

e) 2-(4-Fluorophenyl)-3-bromopyrazolo[1,5-a]pyridine

To a solution of 2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylicacid (0.96 g, 3.75 mmol) in dry DMF (10 mL) was added sodium bicarbonate(0.95 g, 11.3 mmol) followed by N-bromosuccinimide (0.667 g, 3.75 mmol)and the mixture was stirred at room temperature under a nitrogenatmosphere for about 90 min. The mixture was poured into water (300 mL)and the resulting solid was collected by filtration and washed withwater. The solid was dissolved in 10:1 chloroform:methanol (10 mL) andfiltered through a pad (0.5 cm) of silica gel using 10:1chloroform:methanol as eluent. The filtrate was evaporated to leave thetitle compound as a tan solid, 0.87 g (80%). ¹H NMR (d6 DMSO) δ 8.7 (d,1H, J=6.9 Hz), 8.02 (dd, 2H, J=8.7, 5.7 Hz), 7.61 (d, 1H, J=8.4 Hz),7.40 (t, 1H, J=6 Hz), 7.38 (t, 2H, J=9 Hz), 7.04 (t, 1H, J=6.9 Hz). MS(+ve ion electrospray) 293 (100), (MH⁺).

f) 2-Fluoropyridin-4-ylboronic Acid

To a stirred solution of n-butyl lithium (3.2 mL, 2.5M, 8.0 mmol) in drydiethyl ether (20 mL) at −78° C. was added a solution of2-fluoro-4-iodopyridine (1.5 g, 6.7 mmol) in dry ether (10 mL) and thereaction mixture was stirred at −78° C. for 10 min. Tributyl borate (2.4mL, 2.01 g, 8.7 mmol) was added and the reaction mixture was allowed tostir to room temperature over 2 hours. Water (5 mL) was added followedby 2N aqueous sodium hydroxide solution (10 mL) to dissolve the solids.The organic phase was separated. The aqueous phase was acidified to pH 3using 6N HCl and the resulting white solid was collected by filtrationand dried under vacuum to give the title compound, 0.74 g (78%). ¹H NMR(DMSO-d6) δ 8.65 (s, 2H), 8.21 (d, 1H, J=4.8 Hz), 7.59 (t, 1H, J=4.8Hz), 7.37 (d, 1H, J=1.8 Hz).

g) 2-(4-Fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]-pyridine

A solution of 3-bromo-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine (1.30g, 4.5 mmol), 2-fluoro-4-pyridinylboronic acid (694 mg, 4.9 mmol) anddichlorobis(triphenylphosphine)-palladium (316 mg, 0.45 mmol) indimethylformamide (DMF) (100 mL) was placed in a pre-heated oil bath at110° C. To the reaction was added, in a dropwise manner, 2M aqueoussodium carbonate (4.5 mL, 9.0 mmol). The reaction was allowed to stirfor 2 hours and then cooled to room temperature and filtered through apad of Celite. The Celite pad was washed with ethyl acetate and thefiltrate was concentrated to dryness at 50° C. under vacuum. The residuewas partitioned between ethyl acetate and water. The layers wereseparated and the organic phase was dried over anhydrous magnesiumsulfate. The drying agent was removed by filtration and the filtrate wasconcentrated and purified by silica gel chromatography to yield thetitle compound (378 mg, 1.23 mmol, 27%). ¹H NMR (CDCl3): δ 8.57(d, 1H,J=6.9 Hz), 8.22(d, 1H, J=5.4 Hz), 7.7(d, 1H, J=9.0 Hz), 7.75(m, 2H),7.33(m, 1H), 7.14(m, 3H), 6.95(m, 2H). MS (ES+ve) 308 (100, M⁺).

h) In a sealed-tube was combined2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)-pyrazolo[1,5-a]pyridine (30mg, 0.10 mmol) and histamine (40 mg, 0.36 mmol), and the reaction wasplaced in a pre-heated oil bath at 140° C. The reaction was stirred at140° C. until consumption of starting material was indicated by TLCanalysis (50% ethyl acetate in hexanes). The contents of the sealed-tubewere transferred to a flask and concentrated to dryness at 50° C. underhigh vacuum. The residue was purified by silica gel chromatography toyield the title compound, 23 mg (0.06 mmol, 60%). ¹H NMR (d₆-dmso): δ11.8 (s, 1H), 8.73 (d, 1H, J=6.8 Hz), 7.94 (d, 1H, J=5.3 Hz), 7.63 (d,1H, J=9.3 Hz), 7.57 (dd, 2H, J=5.3, 8.6 Hz), 7.48 (s, 1H), 7.30 (t, 1H,J=7.6 Hz), 7.23 (t, 2H, J=9.0 Hz), 6.97 (t, 1H, J=6.8 Hz), 6.75 (s, 1H),6.57 (m, 1H, J=5.3 Hz), 6.44 (s, 1H), 6.33 (d, 1H, J=5.3 Hz), 3.41 (q,2H, J=6.6 Hz), 2.7 (t, 2H, J=6.6 Hz). MS (ES+ve): 399.1 (50, M+), 305.3(90), 169.4 (100).

EXAMPLE 2N-Butyl-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine

In a similar manner as described in Example 1(h), using butylamine inplace of histamine, was obtained the title compound. ¹H NMR (CD₂Cl₂): δ8.49 (d, 1H. J=7.2 Hz), 8.01 (d, 1H, J=5.2 Hz), 7.62 (m, 3H), 7.21(m,1H), 7.07(t, 2H, J=8.8 Hz), 6.85 (m, 2H), 6.54 (dd, 1H. J=4.8, 0.8 Hz),6.32 (s, 1H), 3.16 (quart, 2H, J=6.4 Hz), 1.53 (quint, 2H, J=7.2 Hz),1.37 (sext, 2H, J=Hz), 0.92 (t, 3H, J=7.2 Hz). MS (ES+ve) 361 (100, M⁺).

EXAMPLE 33-(4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinylamino)-1-propanol

In a similar manner as described in Example 1(h), using3-hydroxypropylamine in place of histamine, was obtained the titlecompound. ¹H NMR (CD₂Cl₂): δ 8.55 (d, 1H, J=6.9 Hz), 8.04 (d, 1H, J=5.4Hz), 7.66 (m, 3H), 7.26 (m, 2H), 7.13 (t, 2H, J=8.7 Hz), 6.90 (t, 1H,J=6.9 Hz), 6.57 (d, 1H, J=5.1 Hz), 6.43 (s, 1H), 4.50 (t, 1H, J=5.7 Hz),3.66 (t, 2H, J=5.7 Hz), 3.55 (quart, 2H, J=6.0 Hz), 1.76 (quint, 2H,J=5.7 Hz). MS (ES+ve): 363 (100, M⁺).

EXAMPLE 4N¹-4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinyl-1,3-propanediamine

In a similar manner as described in Example 1(h), using1,3-diaminopropane in place of histamine, was obtained the titlecompound. ¹H NMR (CD₂Cl₂): δ 8.55(d, 1H, J=5.4 Hz), 8.08(d, 1H, J=3.9Hz), 7.69(m, 3H), 7.25 (dd, 1H, J=5.7, 8.7), 7.12(t, 2H, J=6.6 Hz),6.9(t, 1H, J=6.9 Hz), 6.59(d, 1H, J=5.7 Hz), 6.4(s, 1H), 5.02(m, 1H),3.33(q, 2H, J=5.1 Hz), 2.82(t, 2H, J=5.4 Hz), 1.72(m, 2H, J=5.4 Hz). MS(ES+ve): 362 (100, M⁺).

EXAMPLE 54-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-hexyl-2-pyridinamine

In a similar manner as described in Example 1(h), using hexylamine inplace of histamine, was obtained the title compound. ¹H NMR(acetone-d₆): δ 8.67 (d, 1H, J=7.2 Hz), 8.05 (d, 1H, J=5.4 Hz), 7.72 (m,3H), 7.33 (dd, 1H, J=7.2, 8.4 Hz), 7.21 (t, 2H, J=9.0 Hz), 7.00 (td, 1H,J=6.9, 0.9 Hz), 6.50 (s, 1H), 6.49 (d, 1H, J=5.1 Hz), 5.85 (t, 1H, J=5.1Hz), 3.34 (quart, 2H, J=6.0 Hz), 1.61 (quint, 2H, J=6.9 Hz), 1.36 (m,6H), 0.92 (t, 3H, J=2.4 Hz). MS (ES+ve): 389 (100, M⁺).

EXAMPLE 64-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(4-methoxybenzyl)-2-pyridinamine

In a similar manner as described in Example 1(h), using4-methoxybenzylamine in place of histamine, was obtained the titlecompound. ¹H NMR (Dimethyl-d₆ sulfoxide): δ 8.79 (d, 1H, J=7.2 Hz), 7.98(d, 1H, J=5.4 Hz), 7.62 (dd, 2H, J=5.4, 8.4 Hz), 7.53 (d, 1H, J=9.0 Hz),7.29 (m, 5H), 7.04 (quart, 2H, J=5.7 Hz), 6.92 (d, 2H, J=8.7 Hz), 6.51(s, 1H), 6.38 (d, 1H, J=5.1 Hz).

EXAMPLE 74-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-pyridinylmethyl)-2-pyridinamine

In a similar manner as described in Example 1(h), using3-(aminomethyl)-pyridine in place of histamine, was obtained the titlecompound. ¹H NMR (acetone-d₆): δ 8.50 (d, H. J=6.8 Hz), 8.32 (d, H,J=4.0 Hz), 7.90 (d, H, J=5.2 Hz), 7.63 (d, H, J=7.6 Hz), 7.52 (m, H),7.46 (d, H, J=9.2 Hz), 7.16 (m, H), 7.04 (t, H, J=8.8 Hz), 6.85 (t, H,J=6.4 Hz), 6.45 (s, H), 6.37 (d, H, J=4.4 Hz). MS (ES+ve): 396 (60, M⁺),109 (100).

EXAMPLE 84-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-2-pyridinamine

In a similar manner as described in Example 1(h), using propylamine inplace of histamine, was obtained the title compound. ¹H NMR(acetone-d₆): δ 8.67 (d, 1H, J=7.2 Hz), 8.05 (d, 1H, J=5.1 Hz), 7.72 (m,3H), 7.35 (dd, 1H, J=6.9, 9.0 Hz), 7.22 (t, 2H, J=9.0 Hz), 7.03 (t, 1H,J=6.6 Hz), 6.51 (s, 1H), 6.50 (d, H, J=7.2 Hz), 5.84 (m, 1H), 3.31(quart, 2H, J=6.6 Hz), 1.63 (sext, 2H, J=7.2 Hz), 0.98 (t, 3H, J=Hz). MS(ES+ve): 347 (100, M⁺).

EXAMPLE 92-(4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinylamino)-1-ethanol

In a similar manner as described in Example 1(h), using2-hydroxyethylamine in place of histamine, was obtained the titlecompound. ¹H NMR (DMSO-d6): δ 8.79 (d, 1H, J=6.9 Hz), 7.96 (d, 1H, J=5.4Hz), 7.69 (d, 1H, J=9.0 Hz), 7.62 (m, 2H), 7.36 (dd, 1H, J=8.7, 6.9 Hz),7.29 (m, 2H), 7.03 (t, 1H, J=6.6 Hz), 6.56 (m, 2H), 6.36 (d, 1H. J=5.1Hz), 3.53 (t, 2H, J=5.7 Hz), 3.34 (m, 2H). MS (ES+ve): 349 (100, M⁺). MS(ES+ve): 437 (100, M⁺).

EXAMPLE 10N-Benzyl-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine

In a similar manner as described in Example 1(h), using benzylamine inplace of histamine, was obtained the title compound. ¹H NMR(acetone-d₆): δ 8.65 (d, 1H, J=6.9 Hz), 8.06 (d, 1H, J=5.1 Hz), 7.70 (m,2H), 7.54 (d, 1H, J=8.7 Hz), 7.31 (m, 7H), 7.01 (t, 1H, J=6.9 Hz), 6.58(s, 1H), 6.51 (dd, 1H, J=1.5, 5.1 Hz), 6.38 (m, 1H), 4.62 (m, 2H). MS(ES+ve): 395 (100, M⁺).

EXAMPLE 114-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dimethyl-2-pyridinamine

In a similar manner as described in Example 1(h), usingN,N-dimethylamine in place of histamine, was obtained the titlecompound. ¹H NMR (CD₂Cl₂): δ 8.55(d, 1H, J=9.3 Hz), 8.17(d, 1H, J=6.5Hz), 7.64-7.74(m, 3H), 7.25(dd, 1H, J=8, 11.5 Hz), 7.12(t, 2H, J=11.5Hz), 6.90(t, 1H, J=9.3 Hz), 6.57(d, 1H, J=6.5 Hz), 6.54(s, 1H), 3.06(s,6H). MS (ES+ve): 333.2 (100, M⁺).

EXAMPLE 12N-Benzyl-6-fluoro-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine

a)3-(2,6-Difluoro-4-pyridinyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine

A solution of 3-bromo-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine (fromExample 1(e), 570 mg, 1.96 mmol), 2,6-difluoro-4-pyridyl-boronic acid(340 mg, 2.15 mmol) and dichlorobis(triphenylphosphine)palladium (137mg, 0.196 mmol) in DMF (10.0 mL) was placed in a pre-heated oil bath at110° C. To the reaction was added, in a dropwise manner, 2M sodiumcarbonate (2.00 mL, 4.00 mmol). The reaction was allowed to stir for 45minutes before cooling to room temperature and filtering through aCelite 545 pad. The Celite filter was washed with ethyl acetate and thefiltrate was concentrated to dryness at 50° C. under vacuum. The residuewas dissolved in methylene chloride and dried over anhydrous magnesiumsulfate. The drying agent was removed by filtration and the filtrate wasconcentrated and purified by silica gel chromatography to yield thetitle compound (160 mg, 0.492 mmol, 25%). ¹H NMR (CDCl₃): δ 8.53(d, 1H,J=6.8 Hz), 7.67(d, 1H, J=8.8 Hz), 7.53(dd, 2H, J=5.6, 8.0 Hz), 7.31 (t,1H, J=7.6 Hz), 7.11 (t, 2H, J=8.4 Hz), 6.93(t, 1H, J=6.8 Hz), 6.75(s,2H). MS (ES+ve): 326 (90, M⁺).

b) In a sealed-tube was combined3-(2,6-difluoro-4-pyridinyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine(35 mg, 0.11 mmol) and benzylamine (3.0 mL, 2.9 g, 27 mmol), and thereaction was placed in a pre-heated oil bath at 130° C. The reaction wasstirred at 130° C. until consumption of starting material was indicatedby TLC analysis (50% ethyl acetate in hexanes). The contents of thesealed-tube was transferred to a flask and concentrated to dryness at50° C. under high vacuum. The residue was purified by silica gelchromatography to yield the title compound, 18 mg (0.04 mmol, 36%). ¹HNMR (d₆-acetone): δ 8.67(d, 1H, J=6.8 Hz), 7.71(dd, 2H, J=5.6, 8.8 Hz),7.59(d, 1H, J=8.8 Hz), 7.30-7.45(m, 6H), 7.24(t, 2H, J=8.8 Hz), 7.05(t,1H, J=6.8 Hz), 6.73(m, 1H, J=6.0 Hz), 6.46(s, 1H), 6.09(s, 1H), 4.59(d,2H, J=6.0 Hz). MS (ES+ve): 413.1 (100, M⁺).

EXAMPLE 134-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-N-isopropyl-2-pyridinamine

a)2-(4-Fluorophenyl)-3-(2-fluoro-4-pyridinyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

In a similar manner as described in Example 1(g), from2-fluoro-4-pyridylboronic acid and3-bromo-2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine(Example 19(d)) was obtained the title compound. ¹H NMR (CDCl₃): δ8.85(s, 1H), 8.22(d, 1H, J=5.2 Hz), 7.70 (d, 1H, J=9.6 Hz), 7.52(dd, 2H,J=5.2, 8.4 Hz), 7.38(d, 1H, 9.6 Hz), 7.09(t, 2H, J=8.4 Hz), 6.90(s, 1H).MS (ES+ve): 376 (100, M⁺).

b) In a similar manner as described in Example 1(h) using2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)-6-trifluoromethylpyrazolo[1,5-a]pyridineand isopropylamine was obtained the title compound. ¹H NMR (d₆-acetone):δ 9.12(s, 1H), 8.04(d, 1H, J=5.1 Hz), 7.85(d, 1H, J=9.3 Hz), 7.70 (dd,2H, J=5.4, 8.7 Hz), 7.50(d, 1H. J=9.3 Hz), 7.21(t, 2H, J=8.7 Hz),6.49(s, 1H), 6.45(d, 1H, J=5.1 Hz), 5.63(m, 1H), 4.04(m, 1H), 1.20 (d,6H, J=4.8 Hz). MS (ES+ve): 415 (100, M⁺).

EXAMPLE 143-(4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]-pyridin-3-yl]-2-pyridinylamino)-1-propanol

In a similar manner as described in Example 1(h) using2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine(Example 13) and 3-hydroxypropylamine was obtained the title compound.¹H NMR (d₆-DMSO): δ 9.41(s, 1H), 7.95(d, 1H. J=5.2 Hz), 7.78(d, 1H, 9.2Hz), 7.58(dd, 2H, J=5.6, 8.8 Hz), 7.50(d, 1H. J=9.6 Hz), 7.26(t, 2H,J=8.8 Hz), 6.544(m, 1H, J=5.6 Hz), 6.42(s, 1H), 6.33(d, 1H, J=5.6 Hz),6.46(m, 1H), 3.43(m, 2H), 3.22(m, 2H, J=6.8 Hz), 1.62(quint, 2H, J=6.4Hz). MS (ES+ve): 431(100, M⁺).

EXAMPLE 15N-(3-Aminopropyl)-4-[6-bromo-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine

a)6-Bromo-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridine

To a solution of2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]-pyridine(Example 1, 937 mg, 3.05 mmol) in DMF (20 mL) was addedN-bromosuccinimide (651 mg, 3.66 mmol). The reaction mixture was heatedat 60° C. for about 5 hours and then allowed to cool to roomtemperature. Saturated sodium bicarbonate was added and the mixture wasextracted with dichloromethane. The organic extracts were dried overanhydrous magnesium sulfate and the solvents removed under vacuum. Theresidue was purified by silica gel chromatography to give the titlecompound 0.604 g (50%). ¹H NMR (CDCl₃): δ 8.68(s, 1H), 8.20 (d, 1H,J=5.4 Hz), 7.53 (m, 3H), 7.35 (dd, 1H, J=9.3, 1.2 Hz), 7.10 (m, 3H),7.00(s, 1H). MS (ES+ve) 387 (50, M⁺, M+3).

b) In a similar manner as described in Example 1(h), using6-bromo-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridineand 1,3-diaminopropane was obtained the title compound. ¹H NMR(d₆-acetone): δ 8.94 (s, 1H), 8.06 (d, 1H, J=4.8 Hz), 7.72 (m, 3H), 7.44(dd, 1H, J=1.5, 9.6 Hz), 7.23 (m, 3H), 6.51 (s 1H), 6.48 (dd, 1H, J=1.2,6.3 Hz), 6.08 (m 1H), 3.44 (q, 2H, J=5.7 Hz), 3.31 (t, 2H, J=6.3 Hz),1.90 (quint, 2H, J=6.8 Hz). MS (ES+ve) 440 (100, M⁺, M+3).

EXAMPLE 16N-Butyl-4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidin-amine

A solution of2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-pyrazolo[1,5-a]pyridine(Example 17(c), 0.03 g, 0.085 mmol) in n-butylamine (0.5 mL) was heatedto reflux for 0.25 h. On cooling a white solid deposits which wascollected by filtration, washed with hexane and dried under vacuum togive the title compound as a white solid, 0.029 g (94%). ¹H NMR(DMSO-d₆): δ 0.87 (t, J=7.4 Hz, 3H), 1.31 (sextet, J=7.4 Hz, 2H),1.49(quintet, J=7.2 Hz, 2H), 3.25 (q, J=6.6 Hz, 2H), 6.4 (broad s, 1H),7.06 (t, J=6.8 Hz, 1H), 7.13 (broad s, 1H), 7.29 (t, J=8.8 Hz, 2H), 7.43(t, J=7.8 Hz, 1H), 7.59 (dd, J=5.7, 8.5 Hz, 2H), 8.01 (d, J=5.3 Hz, 1H),8.40 (broad s, 1H), 8.76 (d, J=6.9 Hz, 1H); APESI+MS m/z 362 (M+1)⁻.

EXAMPLE 174-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-propyl)-2-pyrimidinamine

a) 1-(4-Fluorophenyl)-2-(4-(2-methylthio)pyrimidinyl)ethanone

To a stirred solution of 2-methylthio-4-methylpyrimidine (66 g, 0.47mol) and ethyl 4-fluorobenzoate (79 g, 0.47 mol) in dry THF (400 mL) at0° C. under nitrogen was added lithium bis(trimethylsilyl)amide (1N inTHF, 940 mL 0.94 mol) over a 2 h period. The solution was stirred at icebath temperature for 18 h. The solution was poured into 2 L of ice cold0.5 N HCl. A precipitate formed which was filtered off and air dried.Second and third crops of solids were obtained as the precipitate waswashed with water. The combined precipitates were recrystalized fromacetone and water to give product as a yellow solid: 117 g (95%). ¹H NMR(CDCl₃): δ (all in enol form): 3.0 (s, 3H), 6.29 (s, 1H), 7.01 (d, J=5.7Hz, 1H), 7.48 (t, J=8.7 Hz, 2H), 8.20 (dd, J=5.4, 8.8 Hz, 2H), 8.68 (d,J=5.7 Hz, 1H); APESI−MS m/z 261 (M−1)⁻.

b)2-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-pyrazolo[1,5-a]pyridine

A solution of 1-(4-fluorophenyl)-2-(4-(2-methylthio)pyrimidinyl)ethanone(13.0 g, 50 mmol) in isopropanol (300 mL) was warmed to reflux. Asolution of 1-aminopyridinium iodide (14 g, 63 mmol) in water (300 mL)was treated with 2N NaOH (31.5 mL). This solution was added to theketone over a period of two hours while the mixture was heated atreflux. After an additional seven hours, the isopropanol was partiallyevaporated under reduced pressure and the resulting solution wasextracted with dichloromethane (2×300 mL). The dichloromethane extractswere combined, dried (MgSO₄), filtered and the solvent evaporated underreduced pressure to leave a red solid which was purified by silica gelchromatography with dichloromethane to give the title compound as ayellow solid, 4.5 g (26%). ¹H NMR (DMSO-d₆): δ 2.5 (s, 3H), 6.80 (d,J=5.3 Hz, 1H), 7.18 (t, J=6.9 Hz, 1H), 7.36 (t, J=8.8 Hz, 2H), 7.59 (t,J=7.9 Hz, 1H), 7.60 (dd, J=5.7, 8.7 Hz, 2H), 8.38 (d, J=9.1 Hz, 1H),8.40 (d, J=5.3 Hz, 1H), 8.88 (d, J=7.0 Hz, 1H), APESI+MS m/z 337 (M+1).

c)2-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine

To a stirred solution of2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-pyrazolo[1,5-a]pyridine(0.285 g, 0.85 mmol) in dichloromethane (10 mL) was added, dropwise, asolution of (0.257 g, 0.85-1.23 mmol) of 57-86% m-chloroperoxybenzoicacid in dichloromethane (5 mL). After 10 min., the solution was quenchedby the addition of aqueous potassium carbonate (20 mL), and the organicphase was separated. The aqueous phase was further extracted withdichloromethane (2×20 mL) and the dichloromethane phases dried overmagnesium sulfate and concentrated to give a crude white solid.Chromatography on silica gel eluting with a hexane/EtOAc gradient(0-100% EtOAc) gave the title compound as a white solid, 0.213 g (60: ¹HNMR (CDCl₃): δ 3.05 (s, 3H), 7.07-7.11 (m, 2H), 7.25 (d, J=8.5 Hz, 2H),7.55 (t, J=7.8 Hz, 1H), 7.64 (dd, J=5.5, 6.9 Hz, 2H), 8.52 (d, J=5.1 Hz,1H), 8.59 (d, J=6.9 Hz, 1H), 8.84 (d, J=9.0 Hz, 1H); APESI+MS m/z 353(M+1)⁻.

d) In a similar manner as described for Example 16, from2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(0.063 g, 0.18 mmol) and isopropylamine was obtained the title compoundas a white solid, 0.022 g (66%). ¹H NMR (CDCl₃): δ 1.28 (d, J=6.6 Hz,6H), 4.21 (septet, J=6.6 Hz, 1H), 5.02 (broad s, 1H), 6.29 (d, J=5.3 Hz,1H), 6.89 (t, J=6.4 Hz, 1H), 7.12 (t, J=8.6 Hz, 2H), 7.31 (t, J=7.9 Hz,1H), 7.60 (dd, J=5.5, 8.6 Hz, 2H), 8.03 (d, J=5.3 Hz, 1H), 8.38 (d,J=8.9 Hz, 1H), 8.48 (d, J=7.0 Hz, 1H); APESI+MS m/z 348 (M+1).

EXAMPLE 184-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

a) 2-(4-Fluorophenyl)-3-acetylpyrazolo[1,5-a]pyridine

A mixture of 2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (2.00 g, 9.42mmol) in acetic anhydride (20 mL) and conc. H₂SO₄ (2 drops) was stirredand heated at reflux for 30 min. The mixture was cooled to roomtemperature, poured into ice water (300 mL), and basified (pH=10) using1N NaOH(aq). The resulting orange precipitate was collected byfiltration, washed with water, air-dried, then dried under high-vacuumto afford the title compound as an orange solid, 2.60 g (quant.). ¹H NMR(CDCl₃) δ 8.56 (d, 1H, J=6.9 Hz), 8.45 (d, 1H, J=9.3 Hz), 7.62 (m, 2H),7.54 (m, 1H), 7.24 (m, 2H), 7.08 (m, 1H), 2.20 (s, 3H). MS (+ve ionelectrospray) 255 (100), (MH⁺).

b)2-(4-Fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)pyrazolo[1,5-a]pyridine

A mixture of 2-(4-fluorophenyl)-3-acetylpyrazolo[1,5-a]pyridine (1.0 g,3.93 mmol) in N,N-dimethylformamide dimethyl acetal (10 mL) was stirredand heated at reflux for 17 hours. The mixture was cooled to roomtemperature and the volatiles evaporated under reduced pressure. Theresidue was purified by silica gel chromatography (eluded with 1%MeOH/CH₂Cl₂) to afford the title compound as an orange solid, 0.830 g(68%). ¹H NMR (CDCl₃) δ 8.50 (d, 1H, J=6.9 Hz), 8.39 (d, 1H, J=9.0 Hz),7.83 (d, 2H, J=12.6 Hz), 7.73 (m, 2H), 7.39 (m, 1H), 7.20 (m, 2H), 6.93(m, 1H), 5.13 (d, 1H, J=12.5 Hz), 3.10 (s, 3H), 2.56 (s, 3H). MS (+veion electrospray) 310 (90), (MH+).

c) 4-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

A mixture of2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)pyrazolo[1,5-a]pyridine(60 mg, 0.19 mmol), guanidinium hydrochloride (36 mg, 0.38 mmol), andK₂CO₃ (105 mg, 0.76 mmol) in N,N-dimethylformamide (3 mL) was stirred ina 110° C. oil bath for 8 hours. Additional guanidinium hydrochloride (36mg, 0.38 mmol) was added, and the mixture stirred in a 110° C. oil bathfor 16 hours. The mixture was cooled to room temperature, and water (20mL) added. The resulting tan precipitate was collected by filtration,washed with water, air-dried, then dried under high-vacuum to afford thetitle compound, 0.033 g (57%). ¹H NMR (CDCl₃) δ 8.57 (d, 1H, J=6.0 Hz),8.51 (d, 1H, J=8.9 Hz), 7.98 (d, 2H, J=5.7 Hz), 7.64 (m, 2H), 7.46 (m,1H), 7.22 (m, 2H), 7.04 (m, 1H), 6.47 (d, 1H, J=5.8 Hz), 5.76 (s, 2H).MS (+ve ion electrospray) 306 (100), (MH⁺).

EXAMPLE 194-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

a) 1-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone

To a solution of 4-fluoroacetophenone (13.8 g, 0.100 mol) and2-chloro-5-trifluoromethylpyridine (20.0 g, 0.110 mol) intetrahydrofuran (400 mL) was added sodium hydride (95%, 5.56 g, 0.220mol) in several portions. The reaction was stirred at room temperaturefor 72 hours then carefully quenched by the addition of water (300 mL)and diethyl ether (200 mL). The organic layer was separated andextracted with 6N HCl (2×300 mL). The aqueous extracts were cooled to 0°C. and 6N NaOH was used to adjust the solution to pH12. The mixture wasthen extracted with diethyl ether and the combined organic extracts weredried over magnesium sulfate. The drying agent was removed by filtrationand the filtrate was evaporated to dryness to afford the title compoundas a tautomeric mixture, 20.9 g (73%). ¹H NMR (CDCl₃): δ 8.87(s),8.63(s), 8.14(dd, J=5.1, 8.4 Hz), 8.00-7.83(m), 7.51(d, J=8.4 Hz),7.22-7.12(m), 6.13(s), 4.60(s). MS (ES+ve): 284 (100, M⁺+1).

b) 1-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl) pyridyl)ethanone Oxime

To a solution of1-(4-fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone (80.0 g,0.282 mol) in methanol (1 L) at room temperature was added 10% aqueoussodium hydroxide (436 mL, 1.09 mol). The resulting solution was stirredvigorously as solid hydroxylamine hydrochloride (98.0 g, 1.40 mol) wasadded. The mixture was heated to reflux for 2 hours, treated withdecolorizing charcoal while hot, then filtered through Celite while hot.The filtrate was concentrated to one-half its original volume and thencooled to 0° C. with stirring for one hour. The resulting solids werecollected by filtration, washed with water, and dried under vacuum at50° C. overnight to provide the title compound as a light yellow powder,73.9 g (88%). ¹H NMR (DMSO-d₆): δ11.60(s, 1H), 8.86(s, ₁H), 8.14(dd, ₁H,J=2.1, 8.1 Hz), 7.78(dd, 2H, J=5.7, 9.0 Hz), 7.53(d, 1H, J=8.4 Hz),7.23(t, 2H, J=9.0 Hz), 4.40(s, 2H). MS (ES+ve): 299 (70, M⁺+1).

c) 3-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)-2H-azirine

To a solution of1-(4-fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone oxime (25.0g, 0.084 mol) in methylene chloride (400 mL) was added triethylamine(46.7 mL, 0.335 mol). The solution was cooled to 0° C. under a nitrogenatmosphere, and trifluoroacetic anhydride (14.1 mL, 0.100 mol) was addeddropwise. The reaction was stirred for 0.5 hours then quenched withwater. The organic layer was separated and dried over anhydrousmagnesium sulfate. The drying agent was removed by filtration and thesolvent was evaporated from the filtrate to leave an oil. The residuewas loaded onto a silica gel column and eluted with 15% ethyl acetate inhexanes to give the title compound as an oil which solidified onstanding, 19.4 g (82%). ¹H NMR (CDCl₃): δ 8.76(s, 1H), 7.93(dd, 2H,J=5.4, 8.7 Hz), 7.83(dd, 1H, J=2.1, 8.4 Hz), 7.27(t, 2H, J=8.7 Hz),7.21(d, 1H, J=8.1 Hz), 3.54 (s, 1H). MS (ES+ve): 281 (100, M⁺+1).

d) 2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

3-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl) pyridyl)-2H-azirine (40.0 g,0.143 mol) was dissolved in 1,2,4-trichlorobenzene (400 mL) and themixture was heated to 200° C. for 10 hours. The reaction mixture wasthen cooled to room temperature and poured onto a silica gel column. Thecolumn was eluted with hexanes to remove the 1,2,4-trichlorobenzene, andthen with 20% diethyl ether in hexanes to elute the product. The desiredfractions were combined and the solvent was evaporated under reducedpressure to leave the title compound, 28.7 g (71%). ¹H NMR (CDCl₃): δ8.84(s, 1H), 7.98(dd, 2H, J=5.4, 8.7 Hz), 7.65(d, 1H. J=9.3 Hz), 7.28(d,1H, J=9.3 Hz), 7.20(t, 2H, J=8.7 Hz), 6.88(s, 1H). MS (ES+ve): 281 (100,M⁺+1).

e) 2-(4-Fluorophenyl)-3-acetyl-6-trifluoromethylpyrazolo[1,5-a]pyridine

To a mixture of2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine (10.30 g,36.76 mmol) and acetic anhydride (100 mL) was added conc. sulfuric acid(10 drops) and the mixture was stirred and heated at reflux for 1 hour.The reaction mixture was cooled to room temperature and poured into icewater (300 mL). 2N Aqueous sodium hydroxide solution was added to raisethe pH of the solution to about 10 and the resulting orange precipitatewas collected by filtration. The solid was washed with water, air-dried,and then dried under vacuum to afford the title compound as an orangesolid, 11.87 g (quant). ¹H NMR (DMSO-d6): δ 9.58 (s, 1H), 8.41 (d, 1H,J=9.3 Hz), 7.89 (d, 1H, J=9.5 Hz), 7.74 (m, 2H), 7.39 (m, 2H), 2.22 (s,3H). MS (+ve ion electrospray) 323 (70), (MH⁺).

f)2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridine

A mixture of2-(4-fluorophenyl)-3-acetyl-6-trifluoromethylpyrazolo[1,5-a]pyridine(11.85 g, 36.77 mmol) and N,N-dimethylformamide dimethyl acetal (100 mL)was stirred at reflux for 17 hours. The mixture was cooled to roomtemperature and then to 0° C. The resulting orange precipitate wascollected by filtration, washed with cold hexanes, and dried undervacuum to afford the title compound as an orange solid, 10.17 g (73%).¹H NMR (DMSO-d6): δ 9.44 (s, 1H), 8.22 (d, 1H, J=9.4 Hz), 7.75 (m, 2H),7.65 (d, 1H, J=9.5 Hz), 7.56 (d, 1H, J=12.4 Hz), 7.35 (m, 2H), 5.05 (d,1H, J=12.3 Hz), 3.04 (s, 3H), 2.56 (s, 3H). MS (+ve ion electrospray)377 (80), (M+).

g)4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

A mixture of2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine(100 mg, 0.27 mmol), guanidinium hydrochloride (52 mg, 0.54 mmol), andsodium ethoxide (73 mg, 1.08 mmol) in EtOH (4 mL) was stirred at refluxfor 21 hours. Additional guanidine was added in portions to the mixtureuntil starting material was consumed as evidenced by TLC. The reactionmixture was cooled to 0° C. and the resulting precipitate was collectedby filtration, washed with cold EtOH and dried under vacuum to affordthe title compound as a tan solid, 93 mg (92%). ¹H NMR (CD₃COCD₃): δ9.19 (s, 1H), 8.73 (d, 1H, J=9.4 Hz), 8.13 (d, 1H, J=5.2 Hz), 7.78 (m,2H), 7.63 (d, 1H, J=9.5 Hz), 7.34 (m, 2H), 6.41 (d, 1H, J=5.2 Hz), 6.17(s, 1H). MS (+ve ion electrospray) 374 (100), (MH⁺).

EXAMPLE 20N-Benzyl-4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

In a similar manner as described for Example 19g, usingN-benzylguanidine in place of guanidinium hydrochloride was obtained thetitle compound as a tan solid, (quant.). ¹H NMR (CD₃COCD₃): δ 9.09 (s,1H), 8.12 (d, 1H, J=5.1 Hz), 7.69 (m, 2H), 7.24-7.42 (m, 7H), 7.01 (m,1H), 6.34 (d, 1H, J=5.1 Hz), 4.70 (d, 2H, J=6.2 Hz). MS (+ve ionelectrospray) 464 (95), (MH⁺).

EXAMPLE 21N-Cyclopropyl-4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

In a similar manner as described for Example 19g, usingN-cyclopropylguanidine in place of guanidinium hydrochloride wasobtained the title compound as an off-white solid, (77%). ¹H NMR(CD₃COCD₃): δ 9.14 (s, 1H), 8.88 (s, 1H), 8.11 (d, 1H, J=5.0 Hz), 7.73(m, 2H), 7.62 (d, 1H. J=9.4 Hz), 7.30 (m, 2H), 6.62 (s, 1H), 6.37 (s,1H, J=5.1 Hz), 2.87 (m, 1H), 0.80 (m, 2H), 0.60 (m, 2H). MS (+ve ionelectrospray) 414 (100), (MH⁺).

EXAMPLE 224-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-N-(2,2,2-trifluoroethyl)-2-pyrimidinamine

In a similar manner as described for Example 19g, usingN-(2,2,2-trifluoroethyl)guanidine in place of guanidinium hydrochloridewas obtained the title compound as a white solid, (2401%). ¹H NMR(CD₃COCD₃): δ 9.16 (s, 1H), 8.62 (s, 1H), 8.19 (d, 1H, J=5.0 Hz), 7.71(m, 2H), 7.61 (d, 1H, J=9.3 Hz), 7.28 (m, 2H), 7.03 (s, 1H), 6.51 (d,1H, J=4.0 Hz), 4.28 (m, 2H). MS (+ve ion electrospray) 456 (100), (MH+).

EXAMPLE 233-(4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinylamino)-1-propanol

a)4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-N-(3-(4-methoxybenzyloxy)propyl)-2-pyrimidinamine

A mixture of2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridine(Example 19(f) 2.0 g, 5.3 mmol),N-(3-(4-methoxybenzyloxy)-propyl)guanidine (2.7 g, 7.95 mmol), andpotassium carbonate (2.2 g, 15.9 mmol) was stirred inN,N-dimethylformamide (20 mL) in a 100° C. oil bath for 18 hours. Themixture was cooled to room temperature, water (200 mL) was added themixture was extracted with chloroform. The chloroform extracts weredried over anhydrous MgSO₄, filtered, and the solvent was evaporated.The crude material was purified by chromatography on silica gel using30% EtOAc/hexanes as eluent to afford the title compound as a whitesolid, 2.1 g (720/%). ¹H NMR (CD₃COCD₃): δ 9.18 (s, 1H), 8.67 (d, 1H,J=9.4 Hz), 8.15 (d, 1H, J=5.1 Hz), 7.77 (m, 2H), 7.56 (d, 1H, J=9.2 Hz),7.34 (m, 4H), 6.90 (d, 2H, J=8.6 Hz), 6.50 (s, 1H), 6.38 (d, 1H, J=5.1Hz), 4.49 (s, 2H), 3.80 (s, 3H), 3.63 (m, 4H), 1.98 (m, 2H). MS (+ve ionelectrospray) 551 (30), (M+).

b)3-(4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinylamino)-1-propanol

A solution of4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]-N-(3-(4-methoxybenzyloxy)propyl)-2-pyrimidinamine(2.1 g, 3.8 mmol) in 4N HCl/dioxane (5 mL) was stirred at roomtemperature for 4.5 hours, then heated to reflux for 1 hour. The mixturewas cooled to room temperature, neutralized with saturated aqueousNaHCO₃, and extracted with EtOAc. The EtOAc extracts were dried overanhydrous MgSO₄, filtered, and the solvent was evaporated. The residuewas triturated with 2% EtOAc/hexanes to afford a solid which wascollected by filtration and dried to give the title compound as a whitesolid, 1.31 g (80% yield). ¹H NMR (CD₃COCD₃): δ 9.20 (s, 1H), 8.73 (d,1H, J=9.3 Hz), 8.15 (d, 1H, J=5.1 Hz), 7.77 (m, 2H), 7.64 (d, 1H, J=9.9Hz), 7.34 (m, 2H), 6.50 (s, 1H), 6.40 (d, 1H, J=5.1 Hz), 3.60-3.70 (m,4H), 1.88 (m, 2H). MS (+ve ion electrospray) 432 (95), (MH+).

EXAMPLE 24N-Cyclopropyl-4-[6-cyano-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

a) 2-(2-(5-Cyanopyridyl))-1-(4-fluorophenyl)ethanone

To a cooled solution (0° C.) of 6-methylnicotinonitrile (5.0 g, 42 mmol)and ethyl 4-fluorobenzoate (6.2 mL, 42 mmol) in anhydroustetrahydrofuran (50 mL) under N₂ was added lithiumbis(trimethylsilyl)amide (1.0M solution in tetrahydrofuran. 84 mL, 84mmol). The reaction mixture was warmed to room temperature and wasallowed to stir at room temperature for 18 hours. The solvents wereevaporated under reduced pressure and the residue was triturated withether and water. The resulting solid was collected by filtration anddried in vacuo to give the title compound as a yellow solid, 10.2 g(quant.). ¹H NMR (400 MHz, d₆-DMSO) showed a mixture of tautomers.

b) 2-(4-Fluorophenyl)-6-cyanopyrazolo[1,5-a]pyridine

N-Boc-O-mesitylsulfonylhydroxylamine (26.7 g, 84.5 mmol) was added inportions to trifluoroacetic acid at 0° C. The mixture was stirred at 0°C. for 30 minutes and then poured into ice water. The resulting whiteprecipitate was collected by filtration, washed with cold water, anddissolved in dichloromethane (300 mL). The organic solution was driedover anhydrous MgSO₄. The drying agent was removed by filtration and thefiltrate was transferred to a flask. To this solution was added2-(2-(5-cyanopyridyl))-1-(4-fluorophenyl)ethanone (6.77 g, 28.2 mmol)and the reaction mixture was stirred at room temperature for about 24hours. The reaction mixture was washed with water, dried over MgSO₄,filtered through a short pad of silica gel and the solvent evaporatedunder reduce pressure. The residue was purified using chromatography togive the title compound as a brown solid, 2.6 g (39%). ¹H NMR (400 MHz,CDCl₃): δ 6.90 (s, 1H); 7.15, (m, 3H), 7.57 (d, 1H, J=8.0 Hz), 7.93 (dd,2H, J=5.2, 8.4 Hz), 8.82 (s, 1H).

c) 2-(4-Fluorophenyl)-3-acetyl-6-cyanopyrazolo[1,5-a]pyridine

A solution of 2-(4-fluorophenyl)-6-cyanopyrazolo[1,5-a]pyridine (6.7 g,11 mmol) and concentrated sulfuric acid (2 drops) in acetic anhydride(25 mL) was heated, and stirred, at 120° C. under N₂ for 5 hours. Thesolution was cooled to room temperature, diluted with ice water andbasified to pH 11 using 2 N aqueous sodium hydroxide. The solution wasextracted with chloroform (3×), and the combined organic extracts weredried and the solvent was evaporated in vacuo. Trituration with methanolafforded a light brown solid which was collected and dried to give thetitle compound, 1.6 g (840/%). ¹H NMR (400 MHz, d₆-DMSO) δ 2.19 (s, 3H),7.35 (t, 2H, J=8.0 Hz), 7.69 (dd, 2H, J=4.0, 8.0 Hz), 7.86 (dd, 1H,J=4.0, 16 Hz), 8.30 (d, 1H, J=12 Hz), 9.75 (s, 1H). MS (ES+) m/z 280(M⁺+H).

d)2-(4-Fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)-6-cyanopyrazolo[1,5-a]pyridine

A mixture of 2-(4-fluorophenyl)-3-acetyl-6-cyanopyrazolo[1,5-a]pyridine(1.6 g, 5.6 mmol) and dimethylformamide-dimethylacetal (15 mL) wasstirred and heated at 130° C., under N₂, overnight. The solution wascooled and the resulting solid was collected by filtration and rinsedwith acetone. The filtrate was evaporated and the resulting solid waspurified using chromatography. The product solids were combined toafford the title compound as a brown solid, 1.3 g (68%). ¹H NMR (300MHz, d₆-DMSO) showed a mixture of isomers. MS (ES+) m/z 335 (M⁺+H), 264(M⁺−70).

e)N-Cyclopropyl-4-[6-cyano-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

To a solution of2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)-6-cyanopyrazolo[1,5-a]pyridine(1.3 g, 3.9 mmol) in dimethylformamide (20 mL), under N₂, was addedN-cyclopropylguanidine (0.78 g, 7.8 mmol) and potassium carbonate (1.1g, 7.8 mmol). The mixture was stirred and heated at 100° C. for 17 hoursand then additional N-cyclopropyl-guanidine (0.39 g, 3.9 mmol) andpotassium carbonate (0.55 g, 3.9 mmol) were added. The mixture washeated at 100° C. for an additional 4 hours and then the reactionmixture was cooled and water added. The resulting solid was collected byfiltration. This solid was dissolved in diethyl ether and purified usingchromatography to give the title compound as a yellow solid, 0.39 g(28%). ¹H NMR (400 MHz, d₆-DMSO): δ 0.50 (m, 2H), 0.69 (d, 2H, J=4.0Hz), 2.69 (m, 1H), 6.29 (d, 1H, J=8.0 Hz), 7.34 (t, 2H, J=8.0 Hz), 7.47(d, 1H, J=4.0 Hz), 7.69 (m, 3H), 8.11 (d, 1H, J=4.0 Hz), 8.56 (s, 1H) MS(ES+) m/z 370 (M⁺+H).

EXAMPLE 252-(4-Fluorophenyl)-3-(4-(2-(3-hydroxypropyl)amino)pyrimidinyl)-6-pyrazolo-[1,5-a]pyridinylcarboxamide

A solution of N-(3-hydroxypropyl)guanidine (5.4 mmol) (prepared fromO-methylisourea-hydrochloride (0.597 g, 5.4 mmol) and propanolamine(0.405 g, 5.4 mmol)) in ethanol (15 mL) was added to a solution ofsodium ethoxide (20 mmol) in ethanol (40 mL). To this mixture was addedthe enamine described in Example 19f (1.88 g, 5.0 mmol) and the reactionmixture was heated at reflux for 24 hours. The solvent was evaporatedunder reduced pressure and the residue was partitioned between saturatedammonium chloride solution and 2:1 ethyl acetate:diethyl ether.

The organic phase was dried over anhydrous magnesium sulfate, filteredto remove the drying agent and the solvents were evaporated. Theresulting oil was purified by silica gel chromatography using 90% ethylacetate in hexanes as eluent to give a pyrimidine orthoester compound1.70 g (3.3 mmol). The orthoester described above (1.73 g, 3.40 mmol)was dissolved in acetone (200 mL) containing water (5 mL). To thissolution was added para-toluenesulfonic acid (p-TSA) monohydrate (0.645g, 3.40 mmol) and the reaction was stirred at room temperature for 30minutes. The acetone was removed under reduced pressure and the residuewas dissolved in a tetrahydrofuran:ethyl ether mixture (3:1). Theorganic phase was washed with saturated sodium bicarbonate solution. Theorganic layer was dried over anhydrous magnesium sulfate, filtered andconcentrated to dryness. The residue was triturated with diethyl etherand the solids were collected by filtration to afford an ethyl ester,0.965 g (2.20 mmol) as a white solid. A mixture of the ester describedabove (1.46 g, 2.98 mmol), sodium cyanide (15 mg, 0.30 mmol) and ammoniain methanol (30 mL, 7M solution) was stirred at room temperature for 5days. Water (20 mL) was added and the mixture was stirred in anice-water bath for 30 minutes. The resulting solid was collected byfiltration and dried under vacuum. The solids were then triturated withtetrahydrofuran at 50° C. for 10 minutes, collected by filtration anddried under vacuum to afford the title compound, 0.935 g (2.30 mmol, 77%yield) as a white powder. NMR (d₆-DMSO, 80° C.): δ 9.30 (s, 1H), 8.44(d, 1H, J=9.3 Hz), 8.11 (d, 1H, J=5.1 Hz), 7.87 (d, 1H, J=9.3 Hz),7.6-7.75 (m, 3H), 7.32 (t, 2H, J=9 Hz), 6.85 (m, 1H), 6.30 (d, 1H, J=5.1Hz), 4.25 (m, 1H), 3.56 (m, 2H), 3.43 (q, 2H, J=6.3 Hz), 1.77(pent, 2H,J=6.3 Hz).

Mass (ES+)=407 (1000/%).

EXAMPLE 264-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[2-(1H-imidazol-5-yl)ethyl]-2-pyrimidinamine

A solution of2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-pyrazolo[1,5-a]pyridine(Example 17(c) 0.105 g, 0.31 mmol) and histamine (0.037 g, 0.33 mmol) inxylene (3 mL) was heated at 135° C. for 3 hours. The solvent wasevaporated and the residue was purified on silica using methanol/ethylacetate as eluent to give the title compound as a white solid, 0.044 g(33%).2. ¹H NMR (DMSO-d₆): δ 2.76 (t, J=7.1 Hz, 2H), 3.49 (d, J=6.9 Hz,2H), 6.17 (d, J=4.4 Hz, 1H), 6.8 (broad s, 1H), 7.06 (t, J=6.8 Hz, 1H),7.17 (broad s, 1H), 7.29 (t, J=8.8 Hz, 2H), 7.41 (t, J=7.9 Hz, 1H), 7.51(s, 1H), 7.60 (dd, J=5.6, 8.6 Hz, 2H), 8.03 (d, J=5.1 Hz, 1H), 8.45(broad s, 1H), 8.76 (d, J=6.9 Hz, 1H), 11.8 (broad s, 1H); APESI+MS m/z400 (M+1)⁻.

EXAMPLE 274-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-pyridinylmethyl)-2-pyrimidinamine

In a similar manner as described for Example 16, from2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 17(c) 0.083 g, 0.25 mmol) and 3-aminomethylpyridine wasobtained the title compound as a white solid, 0.071 g (72%). ¹H NMR(CDCl₃): δ 4.72 (d, J=6.1 Hz, 2H), 5.59 (broad s, 1H), 6.38 (d, J=5.4Hz, 1H), 6.86 (t, J=6.8 Hz, 1H), 7.12 (t, J=8.7 Hz, 2H), 7.18 (t, J=7.6Hz, 1H), 7.27 (dd, J=4.9, 7.7 Hz, 1H), 7.58 (dd, J=5.5, 8.4 Hz, 2H),7.72 (d, J=7.6 Hz, 1H), 8.02 (broad s, 1H), 8.06 (d, J=5.3 Hz, 1H), 8.45(d, J=6.8 Hz, 1H), 8.53 (d, J=4.6 Hz, 1H), 8.66 (s, 1H); APESI+MS m/z397 (M+1)⁻.

EXAMPLE 284-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-pyridinylmethyl)-2-pyrimidinamine

In a similar manner as described for Example 16, from2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 17(c), 0.085 g, 0.25 mmol) and 2-aminomethylpyridine wasobtained the title compound as a white solid, 0.047 g (47%). ¹H NMR(CDCl₃): δ 4.82 (d, J=5.7 Hz, 2H), 6.13 (broad s, 1H), 6.35 (d, J=5.3Hz, 1H), 6.87 (t, J=6.7 Hz, 1H), 7.12 (t, J=8.6 Hz, 2H), 7.18-7.23 (m,2H), 7.36 (d, J=7.8 Hz, 1H), 7.59 (dd, J=5.5, 8.6 Hz, 2H), 7.65 (dt,J=1.6, 7.7 Hz, 1H), 8.07 (d, J=5.3 Hz, 1H), 8.18 (broad s, 1H), 8.46 (d,J=7.0 Hz, 1H), 8.60 (d, J=4.9 Hz, 1H); APESI+MS m/z 397 (M+1).

EXAMPLE 294-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(4-pyridinylmethyl)-2-pyrimidinamine

In a similar manner as described for Example 16, from2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 16(c)) and 4-aminomethylpyridine was obtained the titlecompound as a white solid, (80%). ¹H NMR (CDCl₃): δ 4.71 (d, J=6.2 Hz,2H), 5.69 (broad s, 1H), 6.38 (d, J=5.3 Hz, 1H), 6.85 (t, J=6.8 Hz, 1H),7.11 (t, J=8.6 Hz, 3H), 7.33 (d, J=5.5 Hz, 2H), 7.58 (dd, J=5.5, 8.6 Hz,2H), 7.8 (broad s, 1H), 8.06 (d, J=5.3 Hz, 1H), 8.45 (d, J=6.9 Hz, 1H),8.58 (d, J=5.9 Hz, 2H); APESI+MS m/z 397 (M+1)⁻.

EXAMPLE 304-[2-(4-Fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-pentyl-2-pyridinamine

In a similar manner as described in Example 1(h), using pentylamine inplace of histamine, was obtained the title compound. ¹H NMR(acetone-d₆): δ 8.66 (d, 1H, J=6.9 Hz); 8.05 (d, 1H, J=5.1 Hz), 7.73 (m,3H), 7.65 (t, 2H, J=9.0 Hz), 7.22 (t, 2H, J=2.1 Hz), 7.02 (td, 1H,J=6.9, 1.2 Hz), 6.51 (s, 1H), 6.50 (d, 1H, J=5.4 Hz), 5.82 (m, 1H), 3.34(quart, 2H, J=6.3 Hz), 1.63 (quint, 2H, J=6.9 Hz), 1.39 (m, 4H), 0.94(t, 3H, J=6.3 Hz).

EXAMPLE 31N-Butyl-4-[2-(4-fluorophenyl)-6-trifluoromethylpyrazolo-[1,5-a]pyridin-3-yl]-2-pyrimidinamine

In a similar manner as described for Example 19, using N-butylguanidinein place of guanidinium hydrochloride was obtained the title compound asa yellow solid, (37%). ¹H NMR (CD₃COCD₃): δ 9.14 (s, 1H), 8.63 (d, 1H,J=9.3 Hz), 8.09 (d, 1H, J=5.1 Hz), 7.72 (m, 2H), 7.59 (d, 1H, J=9.3 Hz),7.27 (m, 2H), 6.40 (s, 1H), 6.33 (d, 1H, J=4.2 Hz), 3.44 (m, 2H), 1.62(m, 2H), 1.42 (m, 2H), 0.93 (m, 3H). MS (+ve ion electrospray) 430 (95),(MH+).

EXAMPLE 32N-{4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo-[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N-[3-(4-methylpiperazin-1-yl)propyl]amine

To a mixture of the enamine described in Example 19(f) (5.45 g, 14.45mmol) and N-(3-(4-methylpiprazino)propyl)guanidine hydrogen sulfate(12.88 g, 3.0 equiv, 43.4 mmol) in anhydrous DMF (50 mL) under nitrogenwas added powdered K₂CO₃ (2.75 g, 5.0 equiv, 20.0 mmol). The mixture wasstirred and heated at 130° C. for 37 h and then filtered through a glassfritted funnel while warm. The solvent was evaporated under reducedpressure and the residue was triturated with EtOAc/Hexanes (1:10) toafford a solid that was collected by filtration and dried under vacuumto give the desired product as an off-white solid, 5.0 g (67%). ¹H NMR(300 MHz, CDCl₃): δ 1.85 (m, 2H), 2.30 (s, 3H), 2.53 (m, 10H), 3.54 (m,2H), 6.00 (s, 1H), 6.30 (d, 1H), 7.14 (m, 2H), 7.40 (d, 1H), 7.60 (m,2H), 8.08 (d, 1H), 8.49 (d, 1H), 8.81 (s, 1H). MS (ESI+) m/z 514.19(M+H).

EXAMPLE 33[3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo-[1,5-a]pyridin-6-yl]methanol

a)2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde

To a cold (0° C.) solution of phosphorus oxychloride (8.0 mL, 86 mmol)in N,N-dimethylformamide (160 mL) was added2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine (11.0 g,39.3 mmol). The reaction mixture was stirred at room temperature for 72hours, then quenched with ice water. The solid precipitate was collectedon a filter to provide2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde(11.4 g, 94%) as a white solid. R_(f) 0.45 (4:1 hexanes:ethyl acetate);¹H NMR (400 MHz, CDCl₃) δ 10.15 (s, 1H), 8.92 (s, 1H), 8.53 (d, 1H),7.80 (m, 2H), 7.70 (d, 1H), 7.27 (t, 2H).

b)1-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol

To a cold (−78° C.) suspension of2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde(11.4 g, 37.0 mmol) in tetrahydrofuran (100 mL) was addedethynylmagnesium bromide (111 mL, 0.5 M in tetrahydrofuran, 56 mmol).The reaction mixture was warmed to room temperature and stirred for 14hours. The reaction mixture was poured into water and adjusted toneutral pH with 1N aqueous hydrochloric acid. The aqueous mixture wasextracted with ethyl acetate. The combined extracts were washed withwater and brine. The organic layer was dried over magnesium sulfate.Filtration and concentration provided1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(11.9 g, 96%) as a tan solid. R_(f) 0.18 (4:1 hexanes:ethyl acetate); ¹HNMR (300 MHz, CDCl₃) δ 8.81 (s, 1H), 8.15 (d, 1H), 7.75 (m, 2H), 7.35(d, 1H), 7.19 (t, 2H), 5.76 (s, 1H), 2.71 (d, 1H), 2.60 (d, 1H); MSm/335 (M+1).

c)1-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one

To a cold (0° C.) solution of1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(5.00 g, 15.0 mmol) in chloroform (400 mL) was added manganese dioxide(130 g, 1.50 mol). The reaction mixture was stirred at 0° C. for 1.5hours. The reaction mixture was filtered through a pad of Celite. Thefiltrate was concentrated in vacuo to provide1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo-[1,5-a]pyridin-3-yl]-2-propyn-1-one(3.44 g, 69%) as a clear oil. R_(f) 0.39 (4:1 hexanes:ethyl acetate); ¹HNMR (400 MHz, CDCl₃) δ 8.90 (s, 1H), 8.61 (d, 1H), 7.72-7.69 (m, 3H),7.17 (m, 2H), 3.06 (s, 1H); MS m/z 333 (M+1).

d)N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

To a suspension of N-cyclopentylguanidine hydrochloride (2.20 g, 13.5mmol) in ethanol (70 mL) was added sodium ethoxide (4.5 mL, 3 M inethanol, 14 mmol). The mixture was stirred at room temperature for 30minutes, then cooled to 0° C. To this mixture was added1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(3.44 g, 10.4 mmol) portionwise. The reaction mixture was stirred at 0°C. for 30 minutes, followed by room temperature for 15 hours. Thereaction mixture was diluted with water (400 mL). The solid precipitatewas collected on a filter to provideN-cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(4.48 g, 98%) as an orange solid. ¹H NMR (400 MHz, CDCl₃) δ 8.83 (s,1H), 8.50 (d, 1H), 8.11 (d, 1H), 7.63 (m, 2H), 7.43 (d, 1H), 7.16 (t,2H), 6.34 (d, 1H), 5.17 (d, 1H), 4.34 (m, 1H), 2.09 (m, 2H), 1.80-1.55(m, 6H); MS m/z 442 (M+1); mp 155-156° C.

e)N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

To a dry round bottom flask was added sodium metal (1.9 g, 83 mmol).Ethanol (110 mL) was added and allowed to react with sodium at roomtemperature until completely dissolved.N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(4.48 g, 10.1 mmol) was added and the reaction mixture was stirred at60° C. for 18 hours. The reaction mixture was cooled and concentrated invacuo to approximately one-fourth of the original volume. The resultingmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with water and brine, then dried over magnesiumsulfate. Filtration and concentration providedN-cyclopentyl-4-[2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(4.86 g, 92%) as an off-white solid. R_(f) 0.15 (4:1 hexanes:ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ 8.81 (s, 1H), 8.39 (d, 1H), 8.06 (d,1H), 7.62 (m, 2H), 7.47 (d, 1H), 7.14 (t, 2H), 6.32 (d, 1H), 5.12 (d,1H), 4.35 (m, 1H), 3.43 (q, 6H), 2.08 (m, 2H), 1.80-1.51 (m, 6H), 1.21(t, 9H); MS m/z 520 (M+1).

f) Ethyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carboxylate

To a solution ofN-cyclopentyl-4-[2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo-[1,5-a]pyridin-3-yl]-2-pyrimidinamine(1.0 g, 1.9 mmol) in acetone (40 mL) and water (10 mL) was addedp-toluenesulfonic acid monohydrate (915 mg, 4.81 mmol). The reactionmixture was stirred at room temperature for 2 hours. The pH of thereaction mixture was adjusted to slightly basic using saturated aqueoussodium bicarbonate solution. The reaction mixture was concentrated invacuo to one third of the original volume, then diluted with water. Theprecipitate was collected on a filter to provide ethyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carboxylate(722 mg, 85%) as an orange solid. R_(f) 0.15 (4:1 hexanes:ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ 9.22 (s, 1H), 8.38 (d, 1H), 8.08(br, 1H), 7.85 (d, 1H), 7.64 (m, 2H), 7.16 (t, 2H), 6.34 (s, 1H), 5.26(br, 1H), 4.44 (q, 2H), 4.35 (br, 1H), 2.08 (m, 2H), 1.80-1.52 (m, 6H),1.43 (t, 3H); MS m/z 446 (M+1).

g) To a cold (−78° C.) solution of ethyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carboxylate(722 mg, 1.62 mmol) in dichloromethane (14 mL) was addeddiisobutylaluminum hydride (6.5 mL, 1.0 M in hexanes, 6.5 mmol). Theresultant solution was stirred at −78° C. for 1.5 hours. The reactionmixture was poured into saturated aqueous solution Rochelle's salt andstirred at room temperature for 2 hours. The resultant mixture wasextracted with ethyl acetate. The organic layer was washed with waterand brine, then dried over magnesium sulfate. Filtration andconcentration followed by flash chromatography (4:1dichloromethane:acetone) provided[3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-6-yl]methanol(261 mg, 40%) as a white solid. R_(f) 0.41 (4:1dichloromethane:acetone); ¹H NMR (300 MHz, CDCl₃) δ 8.37 (s, 1H), 8.28(d, 1H), 8.00 (d, 1H), 7.56 (m, 2H), 7.23 (d, 1H), 7.10 (t, 2H), 6.26(d, 1H), 5.24 (d, 1H), 4.65 (s, 2H), 4.29 (m, 1H), 3.73 (br, 1H), 2.03(m, 2H), 1.76-1.45 (m, 6H); MS m/z 404 (M+1).

EXAMPLE 34N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-methylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

a)4-[6-(Bromomethyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

To a solution of[3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo-[1,5-a]pyridin-6-yl]methanol(65 mg, 0.16 mmol) in chloroform (1 mL) was added phosphorus tribromide(6 μL, 0.06 mmol). The reaction mixture was stirred at room temperaturefor 2 hours, then quenched with saturated aqueous sodium bicarbonatesolution. The resultant mixture was extracted with dichloromethane. Theorganic layer was washed with water and brine, then dried over sodiumsulfate. Filtration and concentration followed by flash chromatography(19:1 dichloromethane:acetone) provided4-[6-(bromomethyl)-2-(4-fluorophenyl)pyrazolo-[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(32 mg, 43%) as a yellow oil. R_(f) 0.68 (9:1 dichloromethane:acetone);¹H NMR (400 MHz, CDCl₃) δ 8.49 (s, 1H), 8.39 (d, 1H), 8.05 (d, 1H), 7.60(m, 2H), 7.34 (d, 1H), 7.13 (t, 2H), 6.30 (d, 1H), 5.21 (d, 1H), 4.53(s, 2H), 4.33 (m, 1H), 2.07 (m, 2H), 1.78-1.51 (m, 6H); MS m/z 467(M+1).

b)N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-methylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

To a solution of4-[6-(bromomethyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(40 mg, 0.086 mmol) in toluene (5 mL) was added tributyltin hydride (35μL, 0.13 mmol) and 2,2′-azobisisobutyronitrile (2 mg, 0.009 mmol). Thereaction mixture was heated at 95° C. for 3 hours. After cooling thereaction mixture room temperature, Celite was added and the resultantmixture was concentrated in vacuo. Flash chromatography (19:1dichloromethane:acetone) provided a crude material which was trituratedwith ether to provideN-cyclopentyl-4-[2-(4-fluorophenyl)-6-methylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(4 mg, 12%) as a pale yellow solid. R_(f) 0.63 (9:1dichloromethane:acetone); ¹H NMR (300 MHz, CDCl₃) δ 8.37-8.28 (m, 2H),8.00 (br, 1H), 7.60 (m, 2H), 7.23-7.11 (m, 3H), 6.32 (d, 1H), 5.37 (br,1H), 4.36 (m, 1H), 2.40 (s, 3H), 2.07 (m, 2H), 1.82-1.51 (m, 6H); MS m/z388 (M+1).

EXAMPLE 35N-Cyclopentyl-4-[6-[(cyclopentylamino)methyl]-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

To a suspension of4-[6-(bromomethyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(30 mg, 0.064 mmol) in tetrahydrofuran (2 mL) was added cyclopentylamine(730 μL, 7.4 mmol). The reaction mixture was stirred at room temperaturefor 3 hours, then diluted with ethyl acetate. The organic layer waswashed with saturated aqueous sodium bicarbonate solution, water, andbrine. The organic layer was dried over magnesium sulfate. Filtrationand concentration followed by flash chromatography (39:1dichloromethane:methanol to 35:5 dichloromethane:methanol) providedN-cyclopentyl-4-[6-[(cyclopentylamino)methyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(6 mg, 20%) as a light yellow solid. R_(f) 0.56 (35:5dichloromethane:methanol); ¹H NMR (400 MHz, CDCl₃) δ 8.46 (s, 1H), 8.36(d, 1H), 8.04 (d, 1H), 7.60 (m, 2H), 7.37 (d, 1H), 7.12 (t, 2H), 6.30(d, 1H), 5.10 (d, 1H), 4.33 (m, 1H), 3.84 (s, 2H), 3.14 (m, 1H), 2.07(m, 2H), 1.85 (m, 2H), 1.79-1.38 (m, 12H); MS m/z 471 (M+1).

EXAMPLE 364-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

a) 2-(4-Chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone

To a cold (0° C.) solution of 4-chloro-2-picoline (5.0 g, 39 mmol) andethyl 4-fluorobenzoate (6.6 g, 39 mmol) in tetrahydrofuran (100 mL) wasadded lithium bis(trimethylsilyl)amide (80 mL, 1.0 M in tetrahydrofuran,80 mmol) dropwise via a pressure equalizing funnel over 30 minutes. Uponcomplete addition, the cold bath was removed and the resulting solutionwas stirred at room temperature for 15 hours. The reaction mixture wasconcentrated under reduced pressure and methanol was added to thereaction, resulting in the formation of a white precipitate. Theprecipitate was collected by filtration and dried to give2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (9.6 g, 9901%) as awhite solid. ¹H-NMR (DMSO-d₆): δ 7.90 (m, 3H), 7.11 (t, 2H), 6.56 (s,1H), 5.67 (s, 1H), 4.14 (m, 2H); ¹⁹F-NMR (DMSO-d₆): 6-115.67; MS m/z 250(M+1).

b) 2-(4-Chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime

To a solution of 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone(9.6 g, 38 mmol) in methanol (200 mL) was added hydroxylaminehydrochloride (13.5 g, 190 mmol) followed by the addition of a sodiumhydroxide solution (7.8 g, 190 mmol in 50 mL of water). The resultingsuspension was heated at reflux for 2 hours and then allowed to cool toroom temperature. The mixture was concentrated and water was added tothe resulting slurry. A white precipitate formed, which was collected byfiltration, washed with water and dried (magnesium sulfate) to give2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (8.45 g, 84%)as a white solid. ¹H-NMR (DMSO-d₆): δ 11.56 (s, 1H), 8.44 (d, 1H), 7.80(m, 2H), 7.40 (m, 2H), 7.22 (m, 2H), 4.29 (s, 2H); ¹⁹F-NMR (DMSO-d₆): δ−113.44; MS m/z 265 (M+1).

c) 5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine

To a solution of 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanoneoxime (8.0 g, 30 mmol) in 1,2-dimethoxyethane (50 mL) at 0° C. was addedtrifluoroacetic anhydride (6.3 g, 30 mmol), keeping the temperaturebelow 10° C. during the addition. After the addition was complete, thereaction was warmed to room temperature. The solution was then cooled to4° C. and a solution of triethylamine (8.4 mL, 60 mmol) in1,2-dimethoxyethane (20 mL) was added over a period of 0.5 hours. Themixture was allowed to warm to room temperature and was stirred for 1.5hours. To this mixture was added iron(II) chloride (40 mg) and thereaction was heated at 75° C. for 15 hours. The reaction mixture waspoured into water (300 mL). The resulting suspension was extracted withethyl acetate. The combined organics were dried (magnesium sulfate),filtered and concentrated to a solid residue. This residue was purifiedby flash chromatography (1:1 ethyl acetate-hexane) to give5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (4.2 g, 57%) as awhite solid. ¹H-NMR (CDCl₃): δ 8.36 (d, 1H), 7.93 (q, 2H), 7.49 (d, 1H),7.15 (t, 2H), 6.70 (dd, 1H), 6.69 (s, 1H); ¹⁹F-NMR (CDCl₃): 8-113.30; MSm/z 247 (M+1).

d) 5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde

Phosphorous oxychloride (0.6 mL, 6.4 mmol) was added toN,N-dimethylformamide (10 mL) and the resulting mixture stirred at roomtemperature for 10 minutes.5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (1.0 g, 4.1 mmol) wasadded and the reaction mixture was stirred at room temperature for 12hours. The reaction mixture was poured into ice-water and neutralized topH 7 with aquous ammonium hydroxide. The resulting slurry was extractedwith dichloromethane (3×40 mL). The combined organics were washed withbrine, dried (magnesium sulfate), filtered and concentrated to give,after recrystallization from acetonitrile,5-chloro-2-(4-fluorophenyl)pyrazolo [1,5-a]pyridine-3-carbaldehyde (0.95g, 85%) as a white solid. ¹H-NMR (CDCl₃): δ10.07 (s, 1H), 8.49 (d, 1H),8.44 (d, 1H), 7.78 (q, 2H), 7.22 (t, 2H), 7.07 (dd, 1H); MS m/z 275(M+1).

e)1-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-one

To a solution of5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (0.93g, 3.4 mmol) in tetrahydrofuran (20 mL) at −78° C. was addedethynylmagnesium bromide (16 mL, 0.5 M in tetrahydrofuran, 8.0 mmol).The mixture was allowed to warm to room temperature and stirred for 1hour. Water was added to the reaction and the resulting mixture wasextracted with ethyl acetate. The ethyl acetate phase was dried(magnesium sulfate), filtered and concentrated to a solid residue. Thisresidue was dissolved in dichloromethane (50 mL) and manganese dioxide(5 g) was added. This slurry was stirred at room temperature for 2hours. The manganese dioxide was removed by filtration and the filtratewas concentrated to a solid. This solid was purified by flashchromatography (dichloromethane) to give1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-one(0.63 g, 62% for two steps) as a white solid. ¹H-NMR (CDCl₃): δ 8.52 (d,1H), 8.47 (d, 1H), 7.69 (q, 2H), 7.18 (t, 2H), 7.07 (dd, 1H), 3.00 (s,1H); ¹⁹F-NMR (CDCl₃): δ −111.69; MS m/z 299 (M+1).

f)4-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

To a solution of1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-one(0.61 g, 2.0 mmol) in N,N-dimethylformamide was added cyclopentylguanidine hydrochloride (0.67 g, 4.1 mmol) followed by anhydrouspotassium carbonate (0.57 g, 4.1 mmol). The resulting mixture was heatedat 80° C. for 12 hours. Upon cooling to room temperature, water wasadded. The mixture was extracted with ethyl acetate. The ethyl acetatephase was washed with brine, dried (magnesium sulfate), filtered andconcentrated in vacuo. The resulting residue was purified by flashchromatography (1:1 ethyl acetate-hexane) to give, afterrecrystallization from acetonitrile,4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.6 g, 74%) as a white solid. ¹H-NMR (CDCl₃): 68.54 (broad s, 1H), 8.40(d, 1H), 8.04 (d, 1H), 7.60 (q, 2H), 7.16 (t, 2H), 6.88 (dd, 1H), 6.28(d, 1H), 5.22 (d, 1H), 4.40 (m, 1H), 1.4-2.2 (m, 8H); ¹⁹F-NMR (CDCl₃):8-112.5; MS m/z 408 (M+1).

EXAMPLE 37N-Cyclopentyl-4-[2-(4-fluorophenyl)-5-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

To a solution of4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.1 g, 0.25 mmol) in pyrrolidine (5 mL) was addedrac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (46 mg, 0.08 mmol),cesium carbonate (120 mg, 0.38 mmol) and palladium (II) acetate (11 mg,0.05 mmol). The resulting mixture was stirred at 80° C. for 24 hours, atwhich time the reaction was judged complete by thin layerchromatography. The solution was cooled to room temperature and ethylacetate and water were added to the reaction mixture. The phases wereseparated, and the aqueous phase again extracted with ethyl acetate. Thecombined organic phases were dried (magnesium sulfate), filtered andconcentrated. The resulting residue was purified by flash chromatography(1:1 hexanes-ethyl acetate) to giveN-cyclopentyl-4-[2-(4-fluorophenyl)-5-(1-pyrrolidinyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine (60 mg, 54%) as a solid.¹H-NMR (CDCl₃): 68.23 (d, 1H), 7.92 (d, 1H), 7.58 (m, 2H), 7.35 (s, 1H),7.12 (t, 2H), 6.43 (dd, 1H), 6.2 (d, 1H), 5.00 (d, 1H), 4.46 (m, 1H),3.42 (m, 4H), 2.06-1.4 (m, 12H); ¹⁹F-NMR (CDCl₃): δ −113.69; MS m/z 443(M+1).

EXAMPLE 384-[5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

a) 2-(4-Chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone

To a cold (0° C.) solution of 4-chloro-2-picoline (10 g, 78.4 mmol) andethyl 4-methoxybenzoate (14.1 g, 78.4 mmol) in tetrahydrofuran (100 mL)was added lithium bis(trimethylsilyl)amide (157 ml 1.0 M intetrahydrofuran, 157 mmol) dropwise via a pressure equalizing funnelover half an hour. Upon complete addition, the ice bath was removed andthe resulting solution was heated at 45° C. for 15 hours. The mixturewas cooled to room temperature, and the solution was concentrated.Methanol was added to quench the reaction, resulting in the formation ofa yellow precipitate. The precipitate was collected by filtration anddried to give the product as a mixture of enol and ketone tautomers. MSm/262 (M+1).

b) 2-(4-Chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone Oxime

To a solution of 2-(4-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone inmethanol (200 mL) was added hydroxylamine hydrochloride (27.2 g, 392mmol) followed by the addition of a sodium hydroxide solution (15.7 g,392 mmol in 50 mL of water). The resulting suspension was heated atreflux for 1 hour and then allowed to cool to room temperature. Themixture was concentrated and water was added to the resulting slurry. Awhite precipitate formed, which was collected by filtration, washed withwater and dried to give2-(4-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanone oxime (11.8 g) as awhite solid. ¹H NMR (CDCl₃): δ 8.47 (d, 1H), 7.72 (d, 2H), 7.36 (d, 1H),7.19 (dd, 1H), 6.91 (d, 2H), 4.43 (s, 2H), 3.84 (s, 3H); MS m/z 277(M+1).

c) 5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine

To a solution of 2-(4-chloro-2-pyridinyl)-1-(4-methoxyphenyl)ethanoneoxime (11.8 g, 42.6 mmol) in 1,2-dimethoxyethane (200 mL) at 0° C. wasadded trifluoroacetic anhydride (6.3 mL, 44.8 mmol), keeping thetemperature below 10° C. during the addition. After the addition wascomplete, the reaction was warmed to 15° C. The solution was then cooledto 4° C. and a solution of triethylamine (12.5 mL 89.5 mmol) in1,2-dimethoxyethane (15 mL) was added over a period of 0.5 hours. Themixture was allowed to warm to room temperature and was stirred at roomtemperature for 5 hours. To this mixture was added iron(II)chloride(0.11 g, 0.85 mmol) and the reaction was heated at 75° C. for 15 hours.The reaction mixture was poured into water (300 mL). The resultingsuspension was extracted with ethyl acetate. The organic phase was dried(magnesium sulfate), filtered and concentrated to a solid. This solidwas recrystallized from methanol to give5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine (6.64 g, 600/%) aswhite needles. ¹H NMR (CDCl₃): δ 8.35 (d, 1H), 7.86 (d, 2H), 7.46 (d,1H), 6.97 (d, 2H), 6.67 (d, 1H), 6.65 (s, 1H), 3.85 (s, 3H); MS m/z 259(M+1).

d) 5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde

To N,N-dimethylformamide (20 mL) at 0° C. was added phosphorousoxychloride (0.54 mL, 7.8 mmol). After the addition was complete, themixture was warmed to room temperature and stirred for 1 hour. To thiswas added 5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine (1.0 g,3.86 mmol) and the resultant solution was stirred 2 hours. Water wasadded, followed by dichloromethane. The aqueous layer was extracted withdichloromethane. The combined organics were washed with brine, driedover magnesium sulfate, filtered and concentrated. A white crystallinecompound,5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (0.9g, 81%), was obtained. ¹H NMR (CDCl₃): δ 10.12 (s, 1H), 8.52 (d, 1H),8.47 (d, 1H), 7.76 (d, 2H), 7.11-7.06 (m, 3H), 3.93(s, 3H); MS m/z 287(M+1).

e)1-[5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol

To a cold (−78° C.) suspension of5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (0.90g, 3.14 mmol) in tetrahydrofuran (50 mL) was added ethynylmagnesiumbromide (7.5 mL, 0.5 M in tetrahydrofuran, 3.77 mmol) dropwise. Thereaction mixture was stirred at −78° C. for 1 hour, then at roomtemperature for 4 hours. The resultant solution was poured intosaturated aqueous sodium bicarbonate and extracted with ethyl acetate.The organic layer was washed with water and brine and the combinedorganics were dried over magnesium sulfate. Filtration and concentrationprovided1-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(1.05 g, 100%) as a white solid. ¹H NMR (CDCl₃) δ 8.40 (d, 1H), 8.05 (s,1H), 7.72 (d, 2H), 7.05 (d, 2H), 6.80 (dd, 1H), 5.78 (s, 1H), 3.91 (s,3H), 2.74 (s, 1H), 2.53 (s, 1H); MS m/z 313 (M+1).

f)1-[5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one

To a solution of1-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(1.05 g, 3.14 mmol) in chloroform (100 mL) was added manganese dioxide(6.82 g, 78.5 mmol). The reaction mixture was stirred at, roomtemperature for 3.5 hours. The suspension was filtered through a pad ofCelite and the filtrate was concentrated to give1-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(0.99 g, 100%) as a pale yellow solid. ¹H NMR (CDCl₃) 68.50 (d, 1H),8.46 (d, 1H), 7.64 (d, 2H), 7.04 (dd, 1H), 6.98 (d, 2H), 3.87 (s, 3H),2.99 (s, 1H); MS m/z 295 (M+1).

g)4-[5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

Sodium ethylate (0.7 mL (2.09 mmol), 21% in ethanol) and cyclopentylguanidine hydrochloride (0.47 g, 2.88 mmol) were added sequentially toethanol (30 mL). The resulting solution was stirred at room temperaturefor 30 minutes.1-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(0.5 g, 1.61 mmol) was added, and the suspension was stirred at roomtemperature for 2 days. The reaction was quenched by the addition ofwater. The aqueous phase was extracted by ethyl acetate. The organicswere combined, washed with brine and dried over magnesium sulfate.Filtration and concentration gave a solid. This solid was recrystallizedfrom methanol to give4-[5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.45 g, 66%) as a pale yellow solid. ¹H NMR (CDCl₃) δ 8.59 (broad s,1H), 8.42 (d, 1H), 8.05 (d, 1H), 7.59 (d, 2H), 7.03 (d, 2H), 6.91 (dd,1H), 6.39 (d, 1H), 5.34 (broad s, 1H), 4.42 (m, 1H), 3.92 (s, 3H), 2.17(m, 2H), 1.86-1.60 (m, 6H); MS m/z 420 (M+1).

EXAMPLES 39-49

Using the techniques described above for Examples 1-38, the followingadditional compounds are prepared. Example No. Compound Name Structure39 1-[3-({4-[2-(4-fluorophenyl)- pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinyl}amino)propyl]-2- pyrrolidinone

40 6-Fluoro-4-[2-(4-fluorophenyl)- pyrazolo[1,5-a]pyridin-3-yl]-N-methyl-2-pyridinamine

41 4-[4-Fluoro-2-(4-fluorophenyl)- pyrazolo[1,5-a]pyridin-3-yl]-N,N-dimethyl-2-pyridinamine

42 N-Allyl-4-[2-(4-fluorophenyl)pyrazolo-[1,5-a]pyridin-3-yl]-2-pyridinamine

43 5-[6-Chloro-2-(4-fluorophenyl)- pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyridinamine

44 3-({5-Bromo-4-[2-(4-fluorophenyl)- pyrazolo[1,5-a]pyridin-3-yl]-2-pyridinyl}amino)-1-propanol

45 Methyl 3-(2-{[3-(acetyloxy)propyl]- amino}-4-pyridinyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6- carboxylate

46 3-[2-(Cyclopropylamino)-4- pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6- carboxylic acid

47 3-[2-(Cyclopropylamino)-4- pyrimidinyl]-2-(4-fluorophenyl)-N,N-dimethylpyrazolo[1,5-a]pyridine-6- carboxamide

48 N-Cyclopropyl-3-[2- (cyclopropylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5- a]pyridine-6-carboxamide

49 N-Cyclopentyl-4-[2-(4- fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-6-phenyl-2-pyrimidinamine

EXAMPLE 50 2-(4-Fluorophenyl)-3-(4-pyrimidinyl)-pyrazolo[1,5-a]pyridine

a) 1-(4-Fluorophenyl)-2-(4-pyrimidinyl)-ethanone

To a stirred solution of 4-methylpyrimidine (20.64 g, 0.22 mol) andethyl 4-fluorobenzoate (36.9 g, 0.22 mol) in dry tetrahydrofuran (100mL) at 0° C. under nitrogen was added lithium bis(trimethylsilyl)amide(1M in tetrahydrofuran, 440 mL, 0.44 mol) over a 2 hour period. A whiteprecipitate deposited during the addition and this suspension wasstirred at room temperature overnight. The reaction was diluted with 100mL of water and filtered. The filtrate was washed with water three timesand dried. The solution was diluted with ethyl acetate (100 mL) and theorganic phase separated. The aqueous phase was further extracted withethyl acetate (100 mL). Organic phases were dried over magnesium sulfateand concentrated and combined with the filtrate to give a combined yieldof 47 g (98%) of product. ¹H NMR (CDCl₃) exists as a 2:1 mixture ofenol:keto tautomers: δ enol form: 5.95 (s, 1H), 6.92 (dd, J=1.2, 5.7 Hz,1H), 7.06-7.14 (m, 2H), 7.83 (dd, J=5.4, 8.7 Hz, 2H), 8.40 (d, J=5.7 Hz,1H), 8.8 (s, 1H); keto form: 4.42 (s, 2H), 7.12-7.18 (m, 2H), 7.34 (d,J=4.2 Hz, 1H), 8.06 (dd, J=5.3, 8.8 Hz, 2H), 8.67 (d, J=5.1 Hz, 1H),9.16 (s, 1H); APESI−MS m/215 (M−1)⁻.

b) A solution of 1-(4-fluorophenyl)-2-(4-pyrimidinyl)-ethanone (21.6 g,0.1 mol), 1-aminopyridium iodide (22.2 g, 0.1 mol) and potassiumcarbonate (41.4 g, 0.3 mol) in a mixture of water (300 mL) andisopropanol (300 mL) was heated and stirred at 100° C. for 16 hours. Theisopropanol was removed under vacuum and the resulting aqueous phaseextracted with dichloromethane (5×200 mL). The dichloromethane extractswere combined and the solvent evaporated under reduced pressure to leavea red solid which was purified by silica gel chromatography eluting witha hexane/ethyl acetate to give the title compound as a yellow solid,9.16 g (32%). ¹H NMR (DMSO-d₆): δ 7.07 (d, J=5.4 Hz, 1H), 7.14 (t, J=6.8Hz, 1H), 7.32 (t, J=8.7 Hz, 2H), 7.53 (t, J=7.8 Hz, 1H), 7.60 (dd,J=5.7, 8.7 Hz, 2H), 8.40 (d, J=8.9 Hz, 1H), 8.54 (d, J=5.3 Hz, 1H), 8.83(d, J=7.1 Hz, 1H), 9.16 (s, 1H), APESI+MS m/z 291 (M+1).

EXAMPLE 512-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-pyrazolo[1,5-a]pyridine

a) 1-(4-Fluorophenyl)-2-(4-(2-methylthio) pyrimidinyl)ethanone

To a stirred solution of 2-methylthio-4-methylpyrimidine (66 g, 0.47mol) and ethyl 4-fluorobenzoate (79 g, 0.47 mol) in dry tetrahydrofuran(400 mL) at 0° C. under nitrogen was added lithiumbis(trimethylsilyl)amide (1N in tetrahydrofuran, 940 mL, 0.94 mol) overa 2 hour period. The solution was stirred at ice bath temperature for 18hours. The solution was poured into 2 L of ice cold 0.5 N hydrochloricacid. A precipitate formed which was filtered off and air dried. Secondand third crops of solids were obtained as the precipitate was washedwith water. The combined precipitates were recrystalized from acetoneand water to give product as a yellow solid: 117 g (95%). ¹H NMR(CDCl₃): 8 (all in enol form): 3.0 (s, 3H), 6.29 (s, 1H), 7.01 (d, J=5.7Hz, 1H), 7.48 (t, J=8.7 Hz, 2H), 8.20 (dd, J=5.4, 8.8 Hz, 2H), 8.68 (d,J=5.7 Hz, 1H); APESI−MS m/z 261 (M−1)⁻.

b) A solution of1-(4-fluorophenyl)-2-(4-(2-methylthio)pyrimidinyl)ethanone (13.0 g, 50mmol) in isopropanol (300 mL) was warmed to reflux. A solution of1-aminopyridinium iodide (14 g, 63 mmol) in water (300 mL) was treatedwith 2N sodium hydroxide (31.5 mL). This solution was added to theketone over a period of two hours while the mixture was heated atreflux. After an additional seven hours, the isopropanol was partiallyevaporated under reduced pressure and the resulting solution wasextracted with dichloromethane (2×300 mL). The dichloromethane extractswere combined, dried (magnesium sulfate), filtered and the solventevaporated under reduced pressure to leave a red solid which waspurified by silica gel chromatography with dichloromethane to give thetitle compound as a yellow solid, 4.5 g (26%). ¹H NMR (DMSO-d₆): δ 2.5(s, 3H), 6.80 (d, J=5.3 Hz, 1H), 7.18 (t, J=6.9 Hz, 1H), 7.36 (t, J=8.8Hz, 2H), 7.59 (t, J=7.9 Hz, 1H), 7.60 (dd, J=5.7, 8.7 Hz, 2H), 8.38 (d,J=9.1 Hz, 1H), 8.40 (d, J=5.3 Hz, 1H), 8.88 (d, J=7.0 Hz, 1H), APESI+MSm/z 337 (M+1).

EXAMPLE 522-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-pyrazolo[1,5-a]pyridine

To a stirred solution of2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-pyrazolo[1,5-a]pyridine(0.285 g, 0.85 mmol) in dichloromethane (10 mL) was added, dropwise, asolution of (0.257 g, 0.85-1.23 mmol) of 57-86% m-chloroperoxybenzoicacid in dichloromethane (5 mL). After 10 minutes, the solution wasquenched by the addition of aqueous potassium carbonate (20 mL), and theorganic phase was separated. The aqueous phase was further extractedwith dichloromethane (2×20 mL) and the dichloromethane phases dried overmagnesium sulfate filtered and concentrated to give a crude white solid.Chromatography on silica gel eluting with a hexane/Ethyl acetategradient (0-100% Ethyl acetate) gave the title compound as a whitesolid, 0.213 g (60: ¹H NMR (CDCl₃): δ 3.05 (s, 3H), 7.07-7.11 (m, 2H),7.25 (d, J=8.5 Hz, 2H), 7.55 (t, J=7.8 Hz, 1H), 7.64 (dd, J=5.5, 6.9 Hz,2H), 8.52 (d, J=5.1 Hz, 1H), 8.59 (d, J=6.9 Hz, 1H), 8.84 (d, J=9.0 Hz,1H); APESI+MS m/z 353 (M+1)⁻.

EXAMPLE 532-(4-Fluorophenyl)-7-methyl-3-(4-pyrimidinyl)pyrazolo[1,5-a]pyridine

A solution of2-(4-fluorophenyl)-3-(4-pyrimidinyl)-pyrazolo[1,5-a]pyridine (Example50, 0.2 g, 0.69 mmol) in dry tetrahydrofuran (5 mL) was cooled to −78°C. under nitrogen and lithium diisopropylamide (0.45 mL of a 2M solutionin heptane/tetrahydrofuran/ethylbenzene, 0.9 mmol) was added dropwise.The reaction mixture was stirred for about 10 minutes and methyl iodide(0.2 mL, 4 mmol) was added. The solution was allowed to warm to roomtemperature and stirred for a further 1.5 hours. The reaction mixturewas diluted with diethyl ether (20 mL), water (20 mL) added, and theorganic phase separated. The aqueous phase was further extracted withether (20 mL) and the combined ether phases were dried over anhydrousmagnesium sulfate, filtered and the solvents evaporated to give a yellowsolid. Chromatography on silica gel eluting with 9:1 hexane/ethylacetate gave the title compound, 0.080 g (380/%). ¹H NMR (DMSO-d₆): δ2.72 (s, 3H), 7.05 (d, J=6.3 Hz, 2H), 7.32 (t, J=8.8 Hz, 2H), 7.46 (dd,J=7.0, 8.6 Hz, 1H), 7.61 (dd, J=5.5, 8.6 Hz, 2H), 8.32 (d, J=9.0 Hz,1H), 8.52 (d, J=5.5 Hz, 1H), 9.15 (s, 1H); APESI+MS m/z 305 (M+1)⁻.

EXAMPLE 542-(4-Fluorophenyl)-7-methylthio-3-(4-pyrimidinyl)pyrazolo[1,5-a]pyridine

In a similar manner as described in Example 53, using dimethyl disulfidein place of methyl iodide, was obtained the title compound, (72%). ¹HNMR (DMSO-d₆): δ 2.46 (s, 3H), 7.01 (d, J=7.3 Hz, 1H), 7.06 (d, J=4.7Hz, 1H), 7.33 (t, J=8.8 Hz, 2H), 7.53 (t, J=8.2 Hz, 1H), 7.61 (dd,J=5.5, 8.4 Hz, 2H), 8.22 (d, J=8.8 Hz, 1H), 8.53 (d, J=5.5 Hz, 1H), 9.15(s, 1H); APCI+MS m/336 (M)⁻.

EXAMPLE 552-(4-Fluorophenyl)-7-methylsulfinyl-3-(4-pyrimidinyl)pyrazolo[1,5-a]-pyridine

To a stirred solution of2-(4-fluorophenyl)-7-methylthio-3-(4-pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 54, 0.246 g, 0.73 mmol) in chloroform (20 mL) was added,dropwise, a solution of of m-chloroperbenzoic acid (57-860% o, 0.221 g,0.73-1.1 mmol) in chloroform (10 mL). After 1 hour, the reaction wasquenched by the addition of aqueous potassium carbonate (20 mL), and theorganic phase was separated. The aqueous phase was further extractedwith chloroform (2×20 mL) and the combined chloroform phases were driedover anhydrous magnesium sulfate. The drying agent was removed byfiltration and the solvent was evaporated to give a light brown solid.Chromatography on silica gel eluting with a hexane/ethyl acetategradient (0-30% ethyl acetate) gave the title compound as the majorproduct, 0.170 g (66%). ¹H NMR (DMSO-d₆): δ 3.11 (s, 3H), 7.13 (d, J=5.4Hz, 1H), 7.33 (t, J=8.8 Hz, 2H), 7.50 (d, J=7.0 Hz, 1H), 7.63 (dd,J=5.7, 8.6 Hz, 2H), 7.76 (dd, J=7.4, 8.1 Hz, 1H), 8.50 (d, J=8.8 Hz,1H), 8.60 (d, J=5.5 Hz, 1H), 9.20 (s, 1H); APESI+MS m/z 353 (M+1)⁻.

EXAMPLE 567-(2-Fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-pyrazolo[1,5-a]pyridine

a)7-(2-Fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-pyrazolo[1,5-a]pyridine

To a stirred solution of 2-fluoroethanol (0.128 g, 2 mmol) intetrahydrofuran (5 mL), under nitrogen, was added potassiumtert-butoxide (1M in tert-BuOH. 2.0 mL, 2 mmol) and the resultingsolution stirred for 5 minutes. A solution of7-chloro-2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)pyrazolo[1,5-a]pyridine(0.15 g, 0.4 mmol) in dichloromethane (0.5 mL) was then added dropwiseand the reaction stirred for 16 hours. Dichloromethane (20 mL) and water(20 mL) were added and the aqueous phase was separated. The aqueousphase was further extracted with dichloromethane (2×20 mL) and thecombined organic phases were dried over anhydrous magnesium sulfate andthe solvents evaporated to give a brown solid. Purification on silicagel using 4:1 hexane/ethyl acetate as eluent gave the title compound,0.111 g (70%). ¹H NMR (CDCl₃): δ 2.59 (s, 3H), 4.60 (t, J=4.1 Hz, 1H),4.67 (t, J=4.1 Hz, 1H), 4.87 (t, J=4.1 Hz, 1H), 4.98 (t, J=4.1 Hz, 1H),6.37 (d, J=7.3 Hz, 1H), 6.64 (d, J=5.3 Hz, 1H), 7.13 (t, J=8.6 Hz, 2H),7.37 (t, J=8.2 Hz, 1H), 7.58 (dd, J=5.3, 8.6 Hz, 2H), 8.15 (d, J=8.8 Hz,1H), 8.21 (d, J=5.5 Hz, 1H); APESI+MS m/z 399 (M+1)⁻.

b)7-Chloro-2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)pyrazolo[1,5-a]pyridine

A solution of2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-pyrazolo[1,5-a]pyridine(Example 51, 1.0 g, 3.0 mmol) in tetrahydrofuran (20 mL) was cooled tounder nitrogen. lithium diisopropylamide (2M solution inheptane/tetrahydrofuran/ethylbenzene, 3.0 mL, 6.0 mmol) was addeddropwise. The solution was stirred for 5 minutes then a solution oftoluenesulfonyl chloride (1.2 g, 6.3 mmol) in tetrahydrofuran (5 mL) wasadded dropwise and the reaction mixture was stirred for 1 hour at −78°C. and then allowed to warm to room temperature. Ethyl acetate (30 mL)and water (20 mL) were added and the organic phase was separated. Theaqueous phase was extracted with Ethyl acetate (3×20 mL) and thecombined ethyl acetate phases were dried over magnesium sulfate filteredand the solvent was evaporated to give a brown oil. Purification onsilica gel using 1:1 hexane/dichloromethane as eluent gave7-chloro-2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)pyrazolo[1,5-a]pyridine,0.316 g (28%). ¹H NMR (CDCl₃): δ 2.65 (s, 3H), 6.73 (d, J=5.4 Hz, 1H),7.12-7.25 (m, 3H), 7.39 (dd, J=7.4, 8.9 Hz, 1H), 7.62-7.69 (m, 2H), 8.30(d, J=5.2 Hz, 1H), 8.50 (d, J=8.1 Hz, 1H); APEI+MS m/z 371/373 (M+1)⁻.

EXAMPLE 57N-Butyl-4-[7-(2-fluoroethoxy)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

In a similar manner as described in Example 16, from7-(2-fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 71) and n-butylamine was obtained the title compound, (68%). ¹HNMR (CDCl₃): δ 0.96 (t, J=7.3 Hz, 3H), 1.44 (sextet, J=7.5 Hz, 2H), 1.62(quintet, J=7.5 Hz, 2H), 3.45 (q, J=6.5 Hz, 2H), 4.59 (t, J=4.1 Hz, 1H),4.66 (t, J=4.1 Hz, 1H), 4.86 (t, J=4.1 Hz, 1H), 4.98 (t, J=4.1 Hz, 1H),5.4 (broad s, 1H), 6.26 (d, J=5.3 Hz, 1H), 6.32 (d, J=7.3 Hz, 1H), 7.11(t, J=8.7 Hz, 2H), 7.30 (t, J=7.8 Hz, 1H), 7.60 (dd, J=5.4, 8.6 Hz, 2H),8.01 (d, J=5.1 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H); APESI+MS m/z 424 (M+1)⁻.

EXAMPLE 58N-Benzyl-4-[7-(2-fluoroethoxy)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

In a similar manner as described in Example 16, from7-(2-fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 70) and benzylamine was obtained the title compound, (73%). ¹HNMR (CDCl₃): δ 4.56 (t, J=4.1 Hz, 1H), 4.64 (t, J=4.1 Hz, 1H), 4.72 (d,J=5.7 Hz, 2H), 4.85 (t, J=4.1 Hz, 1H), 4.96 (t, J=4.1 Hz, 1H), 5.7(broad s, 1H), 6.28-6.31 (m, 2H), 7.08-7.16 (m, 3H), 7.26-7.30 (m, 1H),7.34 (d, J=7.9 Hz, 2H), 7.39 (t, J=6.5 Hz, 2H), 7.60 (dd, J=5.5, 8.6 Hz,2H), 7.75 (broad s, 1H), 8.01 (d, J=5.1 Hz, 1H); APESI+MS m/458 (M+1)⁻.

EXAMPLE 592-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine

a)2-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine

A solution of7-chloro-2-(4-fluorophenyl)-3-(4-(2-methylthio)-pyrimidinyl)pyrazolo[1,5-a]pyridine(1.6 g, 4.3 mmol) in dichloromethane (100 mL), was cooled in an icebath. To this solution was added a solution of 2,2,2-trifluoroethanol(1.6 mL, 22 mmol) and potassium tert-butoxide (22 mL of a 1M solution intert-butanol) in tetrahydrofuran (50 mL). The reaction mixture wassubsequently warmed to 60° C. for 18 h, then poured into cold water andneutralized with 1 N HCl. The phases were separated, and the organicswere washed with water (2×50 mL), dried (magnesium sulfate), filtered,and evaporated under reduced pressure. The residue was purified bysilica gel chromatography with ethyl acetate:hexane (1:2) to give thetitle compound as a yellow solid, 1.6 g (86%): ¹H NMR (CDCl₃): δ 2.65(s, 3H), 4.86 (q, J=8.0 Hz, 2H), 6.56 (d, J=7.4 Hz, 1H), 6.73 (d, J=5.4Hz, 1H), 7.20 (t, J=8.6 Hz, 2H), 7.42 (t, J=8.3 Hz, 1H), 7.65 (dd, J=5.5Hz, 8.8 Hz, 2H), 8.28 (d, J=8.9 Hz, 1H), 8.29 (d, J=5.2 Hz, 1H);APESI+MS m/z 435 (M+1).

b)7-Chloro-2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)pyrazolo[1,5-a]-pyridine

2-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)pyrazolo[1,5-a]pyridine(17 g, 50 mmol) (see Example 51) was dissolved in tetrahydrofuran andcooled to −78° C. in a dry ice/acetone bath. Lithium diisopropylamide(2M solution in tetrahydrofuran, 76 mL 0.152 mol) was added. After 20min, carbon tetrachloride (88 mL, 910 mmol) was added. After 2 h, thesolution was quenched with saturated brine (50 mL), and layersseparated. The organics were washed with saturated brine (100 mL), dried(magnesium sulfate), filtered and concentrated. The residue was purifiedby silica gel chromatography with dichloromethane to give the titlecompound as a yellow solid, 159 (80%). ¹H NMR (CDCl₃): δ 2.67 (s, 3H),4.86 (q, J=8.0 Hz, 2H), 6.57 (d, J=7.4 Hz, 1H), 6.75 (d, J=5.4 Hz, 1H),7.21 (t, J=8.6 Hz, 2H), 7.45 (t, J=8.2 Hz, 1H), 7.65 (dd, J=5.4 Hz, 8.7Hz, 2H), 8.28 (apparent d, J=8.1 Hz, 2H); APESI+MS m/z 371 (M+1).

EXAMPLE 60N-Butyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

In a similar manner as descibed in Example 16, from2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine(Example 72) and n-butylamine was obtained the title compound as a whitesolid, (31%). ¹H NMR (CDCl₃): δ 1.02 (t, J=7.3 Hz, 3H), 1.51 (sextet,J=7.5 Hz, 2H), 1.72 (quintet, J=7.5 Hz, 2H), 3.51 (q, J=7.0 Hz, 2H),4.86 (q, J=8.1 Hz, 2H), 5.2 (broad s, 1H), 6.35 (d, J=5.3 Hz, 1H), 6.52(d, J=7.2 Hz, 1H), 7.17 (t, J=8.7 Hz, 2H), 7.35 (dd, J=7.6, 8.8 Hz, 2H),7.68 (dd, J=5.4, 8.6 Hz, 2H), 8.10 (d, J=5.3 Hz, 1H), 8.21 (d, J=8.9 Hz,1H); APESI+MS m/z 460 (M+1)⁻.

EXAMPLE 61N-Benzyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]-pyridin-3-yl]-2-pyrimidinamine

In a similar manner as described in Example 16, from2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine(Example 72, 0.034 g, 0.076 mmol) and benzylamine was obtained the titlecompound, 0.03 g (80%). ¹H NMR (CDCl₃): δ 4.65 (d, J=5.8 Hz, 2H), 4.72(dd, J=8.1, 16.3 Hz, 2H), 5.6 (broad s, 1H), 6.27 (d, J=5.3 Hz, 1H),6.36 (d, J=7.3 Hz, 1H), 7.07 (t, J=8.6 Hz, 3H), 7.23-7.29 (m, 1H),7.29-7.35 (m, 4H), 7.56 (dd, J=5.7, 8.5 Hz, 2H), 7.7 (broad s, 1H), 8.00(d, J=5.3 Hz, 1H); APESI+MS m/z 494 (M+1)⁻.

EXAMPLE 62N-Cyclopropyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

2-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)-pyrazolo[1,5-a]pyridine(Example 72, 1.4 g, 3.1 mmol) was dissolved in dichloromethane (50 mL)and treated with cyclopropylamine (10 mL, 61 mmol). The solution washeated at reflux for six days, cooled to room temperature and thendiluted with dichloromethane. The solution was washed with saturatedsodium bicarbonate (25 mL) and water (25 mL), dried (magnesium sulfate),filtered and the solvent evaporated under reduced pressure. The residuewas purified by silica gel chromatography with ethyl acetate:hexane(1:1) as eluent to give the title compound as a white solid, 1.1 g(80%): ¹H NMR (acetone-d₆): δ 0.47 (br. s, 2H), 0.66 (br. s, 2H), 2.70(m, 1H), 5.02 (q, J=8.2 Hz, 2H), 6.22 (d, J=5.2 Hz, 1H), 6.41 (br. s,1H), 6.62 (d, J=7.2 Hz, 1H), 7.15 (t, J=8.5 Hz, 2H), 7.33 (t, J=8.1 Hz,1H), 7.60 (m, 2H), 7.94 (d, J=5.1 Hz, 1H), 8.34 (br. s, 1H); APESI+MSm/z 444 (M+1).

EXAMPLE 63N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

2-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)-pyrazolo[1,5-a]pyridine(Example 72, 0.05 g, 0.11 mmol) was dissolved in cyclopentylamine (1 mL)and heated at 60° C. for 18 hours. The reaction mixture was diluted withethyl acetate (40 mL) and extracted with water (2×10 mL). The organiclayer was dried (magnesium sulfate), filtered and the solvent wasevaporated under reduced pressure. The residue was purified on a silicagel preparative chromatography plate (2 mm) with ethyl acetate:hexanes(1:2) as eluent to give the title compound, 0.008 g (15%). ¹H NMR(acetone-d₆): δ 1.60 (m, 4H), 1.75 (m, 2H), 2.04 (m, 2H), 4.32 (m, 1H),5.13 (q, J=8.4 Hz, 2H), 6.23 (br. s, 1H), 6.30 (d, J=4.7 Hz, 1H), 6.73(d, J=7.5 Hz, 1H), 7.25 (t, J=8.7 Hz, 2H), 7.43 (t, J=8.1 Hz, 1H), 7.70(dd, J=5.5 Hz, 8.8 Hz, 2H), 8.04 (d, J=5.1 Hz, 1H), 8.24 (d, J=9 Hz,1H); APESI+MS m/472 (M+1).

EXAMPLE 64N-Cyclohexyl-4-[2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

In a similar manner as described in Example 63 from2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 72) was obtained the title compound, (49%). ¹H NMR(acetone-d₆): 81.3 (m, 5H), 1.60 (m, 1H), 1.80 (m, 2H), 2.00 (m, 2H),3.80 (m, 1H), 5.13 (q, J=8.4 Hz, 2H), 6.12 (s, 1H), 6.30 (s, 1H), 6.73(d, J=7.5 Hz, 1H), 7.25 (t, J=8.7 Hz, 2H), 7.43 (t, J=8.1 Hz, 1H), 7.69(dd, J=5.5 Hz, 8.6 Hz, 2H), 8.04 (d, J=5.1 Hz, 1H), 8.22 (d, J=8.9 Hz,1H); APESI+MS m/z 485 (M+1).

EXAMPLE 653-(4-[2-(4-Fluorophenyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinylamino)-1-propanol

In a similar manner as described in Example 63. From2-(4-fluorophenyl)-7-(2,2,2-trifluoroethoxy)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine(Example 72) was obtained the title compound, (38%). ¹H NMR(acetone-d₆): δ 1.69 (m, 2H), 3.44 (apparent q, J=6.4 Hz, 2H), 3.53 (s,2H), 3.75 (br. s, 1H), 5.01 (q, J=8.4 Hz, 2H), 6.19 (d, J=5.2 Hz, 1H),6.32 (br. s, 1H), 6.62 (d, J=7.5 Hz, 1H), 7.14 (t, J=8.9 Hz, 2H), 7.32(t, J=8.2 Hz, 1H), 7.59 (dd, J=5.6 Hz, 8.6 Hz, 2H), 7.93 (d, J=5.2 Hz,1H), 8.14 (d, J=8.9 Hz, 1H); APESI+MS m/z 462 (M+1).

EXAMPLE 662-(4-Fluorophenyl)-3-(4-(2-methyloxy)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine

2-(4-Fluorophenyl)-7-(2,2,2-trifluoroethoxy)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine (Example 72) (0.05 g, 0.11 mmol) was dissolvedin 2 N ammonia in methanol (20 mL) and the mixture was heated at 80° C.for 18 hours. The reaction mixture was diluted with ethyl acetate (40mL) and extracted with water (2×10 mL). The organic layer was dried(magnesium sulfate), filtered and evaporated under reduced pressure. Theresidue was purified on a silica gel preparative chromatography plate (2mm) with ethyl acetate:hexane (1:2) as eluent to give the titlecompound, 0.034 g (73%). ¹H NMR (CDCl₃) δ 4.12 (s, 3H), 4.86 (q, J=8.0Hz, 2H), 6.56 (d, J=7.4 Hz, 1H), 6.71 (d, J=5.2 Hz, 1H), 7.21 (t, J=8.5Hz, 2H), 7.42 (t, J=8.2 Hz, 1H), 7.65 (dd, J=5.4 Hz, 7.7 Hz, 2H), 8.30(d, J=5.2 Hz, 1H), 8.35 (d, J=8.9 Hz, 1H); APESI+MS m/z 419 (M+1).

EXAMPLE 672-(4-Fluorophenyl)-3-(4-(2-phenyloxy)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine

2-(4-Fluorophenyl)-7-(2,2,2-trifluoroethoxy)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine (Example 72) (0.05 g, 0.11 mmol) was dissolvedin dichloromethane (3 mL) and treated with a solution of phenol (0.1 mL,1.1 mmol) and potassium tert-butoxide (1.2 mL of a 1 N in tert-butylalcohol) in tetrahydrofuran (3 mL). After 30 min at ambient temperature,the reaction was quenched with water and diluted with ethyl acetate (40mL) and extracted with water (2×10 mL). The organic layer was dried(magnesium sulfate), filtered and evaporated under reduced pressure. Theresidue was purified on a silica gel preparative chromatography plate (2mm) with ethyl acetate:hexane (1:2) as eluent to give the titlecompound, 0.032 g (61%). ¹H NMR (CDCl₃): δ 4.81 (q, J=8.0 Hz, 2H), 6.49(d, J=7.4 Hz, 1H), 6.74 (d, J=5.4 Hz, 1H), 7.17 (t, J=7.7 Hz, 1H), 7.23(t, J=8.6 Hz, 2H), 7.32 (d, J=7.7 Hz, 2H), 7.36 (t, J=7.4 Hz, 1H), 7.53(t, J=7.7 Hz, 2H), 7.63 (dd, J=5.4 Hz, 8.6 Hz, 2H), 7.76 (d, J=8.8 Hz,1H), 8.31 (d, J=5.4 Hz, 1H); APESI+MS m/z 481 (M+1).

EXAMPLE 682-(4-Fluorophenyl)-3-(4-(2-(2,2,2-trifluoroethoxy))pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine

In a similar manner as described in Example 56, from2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(ethylsulfinyl)pyrazolo[1,5-a]pyridine(Example 69) and 2,2,2-trifluoroethanol was obtained the title compound,(10%). ¹H NMR (CDCl₃): δ 4.78-4.85 (m, 4H), 6.52 (d, J=7.3 Hz, 1H), 6.75(d, J=5.3 Hz, 1H), 7.16 (t, J=8.6 Hz, 2H), 7.41 (t, J=8.2 Hz, 1H), 7.58(dd, J=5.3, 8.6 Hz, 2H), 8.22 (d, J=8.8 Hz, 1H), 8.25 (d, J=5.3 Hz, 1H);APESI+MS m/z 487 (M+1)⁻.

EXAMPLE 692-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(ethylsulfinyl)-pyrazolo[1,5-a]pyridine

In a similar manner as described in Example 55, from2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-7-(ethylthio)pyrazolo[1,5-a]pyridinewas obtained the title compound. ¹H NMR (CDCl₃): δ 1.25 (t, J=7.5 Hz,3H), 3.00 (s, 3H), 3.33-3.45 (m, 2H), 7.05 (d, J=5.5 Hz, 1H), 7.20 (t,J=8.6 Hz, 2H), 7.54-7.59 (m, 3H), 7.67 (dd, J=7.3, 8.8 Hz, 1H), 8.52 (d,J=5.5 Hz, 1H), 8.25 (t, J=8.4 Hz, 1H); APESI+MS m/z 429 (M+1)⁻.

EXAMPLE 702-(4-Fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-7-(ethylthio)-pyrazolo[1,5-a]pyridine

In a similar manner as described in Example 56, from2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-pyrazolo[1,5-a]pyridineand diethyl disulfide in place of toluenesulfonyl chloride was obtained2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-7-(ethylthio)pyrazolo[1,5-a]pyridine.¹H NMR (CDCl₃): δ 1.46 (t, J=7.4 Hz, 3H), 2.60 (s, 3H), 3.16 (q, J=7.4Hz, 2H), 6.67 (d, J=5.5 Hz, 1H), 6.81 (d, J=7.3 Hz, 1H), 7.13 (t, J=8.6Hz, 2H), 7.35 (t, J=8.1 Hz, 1H), 7.59 (dd, J=5.5, 8.6 Hz, 2H), 8.22 (d,J=5.5 Hz, 1H), 8.28 (d, J=9.0 Hz, 1H).

EXAMPLE 717-(2-Fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)-pyrimidinyl)-pyrazolo[1,5-a]pyridine

In a similar manner as described in Example 55, from7-(2-fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)pyrazolo[1,5-a]pyridinewas obtained7-(2-fluoroethoxy)-2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)pyrazolo[1,5-a]pyridine.¹H NMR (CDCl₃): δ 3.04 (s, 3H), 4.65 (t, J=4.0 Hz, 1H), 4.75 (t, J=4.0Hz, 1H), 4.91 (t, J=4.1 Hz, 1H), 5.06 (t, J=4.1 Hz, 1H), 6.50 (d, J=7.5Hz, 1H), 7.02 (d, J=5.5 Hz, 1H), 7.24 (t, J=8.6 Hz, 2H), 7.54 (t, J=8.3Hz, 1H), 7.62-7.67 (m, 2H), 8.48-8.53 (m, 2H).

EXAMPLE 722-(4-Fluorophenyl)-3-(4-(2-methylsulfinyl)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)-pyrazolo[1,5-a]pyridine

In a similar manner as described in Example 55, from2-(4-fluorophenyl)-3-(4-(2-methylthio)pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine and m-chloroperbenzoic acid was obtained2-(4-fluorophenyl)-3-(4-(2-methylsulfinyl)-pyrimidinyl)-7-(2,2,2-trifluoroethoxy)pyrazolo[1,5-a]pyridine.¹H NMR (CDCl₃): δ 3.03 (s, 3H), 4.85 (q, J=8.0 Hz, 2H), 6.60 (d, J=7.3Hz, 1H), 7.05 (d, J=5.3 Hz, 1H), 7.24 (t, J=7.6 Hz, 2H), 7.52 (t, J=8.2Hz, 2H), 7.60-7.68 (m, 2H), 8.51 (d, J=5.5 Hz, 1H), 8.57 (d, J=8.8 Hz,1H).

EXAMPLE 73 2-(4-Fluorophenyl)-3-(4-pyridyl)-pyrazolo[1,5-a]pyridine

a) 2-(4-Fluorophenyl)-3-(4-pyridyl)-pyrazolo[1,5-a]pyridine

To a solution of 2-(4-fluorophenyl)-3-bromopyrazolo[1,5-a]pyridine (0.2g, 0.68 mmol) and 4-(tributylstannyl)pyridine (0.38 g, 1 mmol) in drytoluene (10 mL) was added tetrakis(triphenylphosphine)palladium (0)(0.03 g, 0.03 mmol) and the mixture was heated at reflux temperatureunder a nitrogen atmosphere for about 48 hours. The mixture was cooledto room temperature and diluted with diethyl ether (40 mL). The mixturewas poured into a 10% aqueous solution of potassium fluoride (20 mL) andthe mixture was stirred for 1 hour. The biphasic mixture was filteredthrough a pad (1 cm) of diatomaceous earth and the organic phase wasseparated. The aqueous phase was extracted with diethyl ether (10 mL)and the combined organic phases are washed with brine, dried overanhydrous magnesium sulfate, filtered and the solvent evaporated underreduced pressure. The residue was purified using silica gelchromatography with 20% ethyl acetate in hexanes, followed by 50% ethylacetate in hexanes, as eluent to give the title compound as an off whitesolid, 0.16 g (80%). ¹H NMR (CDCl₃) δ 8.58 (s, 2H), 8.50 (d, 1H, J=7.2Hz), 7.63 (d, 1H, 9 Hz), 7.52 (m, 2H), 7.27-7.20 (m, 3H), 7.06 (t, 2H,8.7 Hz), 6.86 dt, 1H, J=7, 1 Hz). MS (+ve ion electrospray) 290 (100),(MH⁺).

b) 2-(4-Fluorophenyl)-3-bromopyrazolo[1,5-a]pyridine

To a solution of 2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylicacid (0.96 g, 3.75 mmol) in dry N,N-dimethylformamide (10 mL) was addedsodium bicarbonate (0.95 g, 11.3 mmol) followed by N-bromosuccinimide(0.667 g, 3.75 mmol) and the mixture was stirred at room temperatureunder a nitrogen atmosphere for about 90 minutes. The mixture was pouredinto water (300 mL) and the resulting solid was collected by filtrationand washed with water. The solid was dissolved in 10:1chloroform:methanol (10 mL) and filtered through a pad (0.5 cm) ofsilica gel using 10:1 chloroform:methanol as eluent. The filtrate wasevaporated to leave the title compound as a tan solid, 0.87 g (80%). ¹HNMR (d6 DMSO) δ 8.7 (d, 1H, J=6.9 Hz), 8.02 (dd, 2H, J=8.7, 5.7 Hz),7.61 (d, 1H, J=8.4 Hz), 7.40 (t, 1H, J=6 Hz), 7.38 (t, 2H, J=9 Hz), 7.04(t, 1H, J=6.9 Hz). MS (+ve ion electrospray) 293 (100), (MH⁺).

c) 2-(4-Fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylic Acid

A solution of methyl2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylate (5.0 g, 18.5mmol) in 2N aqueous sodium hydroxide (50 ml) and methanol (30 mL) washeated at reflux for about 3 hours. The mixture was filtered and thefiltrate was washed with diethyl ether (20 mL) and then concentratedunder reduced pressure to about half the original volume. Concentratedhydrochloric acid was added to adjust the pH to about 2 and theresulting solid was collected by filtration and washed with water anddried under vacuum to give the title compound as a white solid, 4.8 g(ca. 100%). ¹H NMR (d6 DMSO) δ 12.43 (s, 1 h), 8.84 (d, 1H, J=6.9 Hz),8.14 (d, 1H, J=9 Hz), 7.82 (m, 2H), 7.57 (t, 1H, J=8.1 Hz), 7.28 (t, 2H,J=9 Hz), 7.15 (td, 1H, J=6.9, 1.2 Hz). MS (+ve ion electrospray) 257(100), (MH⁺).

d) Methyl 2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-3-carboxylate

A stirred solution of methyl 3-(4-fluorophenyl)propiolate (8.02 g, 45mmol) and 1-aminopyridinium iodide (10 g, 45 mmol) in dry acetonitrile(150 mL) was cooled to about 0° C. A solution of1,8-diazabicycloundec-7-ene (13.7 g, 90 mmol) in dry acetonitrile (50mL) was added dropwise over 1 hour. The mixture was allowed to stir atroom temperature for about 18 h. The reaction mixture was cooled in anice bath for about 30 minutes and the precipitate was collected byfiltration and washed with cold acetonitrile (10 mL). The solid wasdried under reduced pressure to give the title compound as a whitesolid, 8.48 g (70%). ¹H NMR (CDCl₃) δ 8.50 (d, 1H, J=8.4 Hz), 8.18 (d,1H, J=8.8 Hz), 7.78 (m, 2H), 7.42 (t, 1H, J=8.4 Hz), 7.13 (t, 2H, J=8.8Hz), 6.97 (td, 1H, J=6.8, 1 Hz). MS (+ve ion electrospray) 271 (100),(MH⁺).

e) Methyl 3-(4-fluorophenyl)propiolate

A solution of 1-(4-fluorophenyl)-2-trimethylsilylacetylene (64 g, 0.33mol) in dry diethyl ether (400 mL) was cooled to 0° C. under a nitrogenatmosphere. To this solution was added, dropwise over 45 minutes, asolution of tetrabutylammonium fluoride (1M in tetrahydrofuran, 330 mL,0.33 mol) via a dropping funnel maintaining the internal temperaturebelow 2° C. The mixture was allowed to warm to room temperature overabout 1 hour. Diethyl ether (300 mL) was added to the mixture and theorganic solution was washed with water, saturated brine and then driedover anhydrous magnesium sulfate. The magnesium sulfate was removed byfiltration and the filtrate was cooled to about −78° C. n-Butyl lithium(1.6M in hexanes, 450 mL, 0.72 mol) was added dropwise via a droppingfunnel over about 1 hour while the temperature was maintained below −66°C. After complete addition the mixture was stirred at −78° C. for about1 hour and then a precooled solution of methyl chloroformate (110 mL,1.4 mol) in dry diethyl ether (200 mL) was added in a continuous streamas fast as possible. The mixture was allowed to cool to −78° C. and theallowed to warm to room temperature over 1.5 h. The organic reactionmixture was washed with water and saturated brine and then dried overanhydrous magnesium sulfate. The solvents are remove under reducedpressure and the residue dried under reduced pressure to give the titlecompound as a brown solid, 36.5 g (61%). ¹H NMR (CDCl3) δ 7.58 (dd, 2H,J=9, 5.4 Hz), 7.07 (t, 2H, J=8.5 Hz), 3.84 (s, 3H). MS (+ve ionelectrospray) 178 (30), (M⁺).

f) 1-(4-Fluorophenyl)-2-trimethylsilylacetylene

4-Fluoroiodobenzene (112 mL, 0.97 mol) and triethylamine (176 mL, 1.26mol) are dissolved in dry tetrahydrofuran (1.2 L) and nitrogen gas wasbubbled through the solution for about 20 min. Copper (I) iodide (1.08g, 5.7 mmol) and bis(triphenyphosphine)palladium dichloride (2.15 g, 3mmol) are added and then trimethylsilylacetylene (178 mL, 1.3 mol) wasadded dropwise over about 40 min with the temperature being maintainedat about 23° C. A large amount of precipitate forms (presumably Et₃NHCl)which necessitates mechanical stirring. Following complete addition ofthe trimethylsilylacetylene the mixture was allowed to stir at roomtemperature for about 18 hours. The mixture was filtered and the solidwashed with cyclohexane. The combined filtrates are concentrated underreduce pressure to give a brown oil. Application of this oil to a pad ofsilica gel followed by elution with cyclohexane gave a yellow solution.Removal of the solvent gave the title compound as a yellow oil; 182.8 g(95%).

EXAMPLE 742-(4-Fluorophenyl)-7-methyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine

a) 2-(4-Fluorophenyl)-7-methyl-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine

In a similar manner as described in Example 73, from2-(4-fluorophenyl)-3-bromo-7-methylpyrazolo[1,5-a]pyridine (0.1 g, 0.33mmol) and 4-(tri-n-butyl)stannylpyridine (0.17 g, 0.46 mmol) wasobtained the title compound as a white solid, 0.016 g (140/%). Thismaterial was dissolved in diethyl ether and treated with HCl in diethylether to afford the corresponding hydrochloride salt. ¹H NMR (DMSO-d6) δ8.74 (d, 2H, J=6.6 Hz), 7.91 (d, 1H, J=8.9 Hz), 7.81 (d, 2H, J=6.6 Hz),7.61 (m, 2H), 7.56 (t, 1H, J=15.9 Hz), 7.34 (t, 2H, J=17.6 Hz), 7.15 (d,1H, J=6.9 Hz), 2.79 (s, 3H). MS (+ve electrospray) 303 (100), (M+).

b) 2-(4-Fluorophenyl)-3-bromo-7-methyl-pyrazolo[1,5-a]pyridine

Following the procedure outlined in Example 73, from2-(4-fluorophenyl)-7-methyl-pyrazolo[1,5-a]pyridine-3-carboxylic acidwas obtained the title compound, ¹H NMR (CDCl₃) δ 8.00 (m, 2H), 7.38 (d,1H, J=8.8 Hz), 7.11 (m, 3H), 6.62 (d, 1H, J=6.9 Hz), 2.71 (s, 3H). MS(+ve electrospray) 306 (25), (MH⁺).

c) 2-(4-Fluorophenyl)-7-methyl-pyrazolo[1,5-a]pyridine-3-carboxylic Acid

In a similar manner as described in Example 73, from methyl2-(4-fluorophenyl)-7-methyl-pyrazolo[1,5-a]pyridine-3-carboxylate wasobtained the title compound as a white solid, ¹H NMR (DMSO-d6) δ 8.08(d, 1H, J=8.8 Hz), 7.84 (m, 2H), 7.76 (m, 1H), 7.53 (m, 1H), 7.30 (t,2H, J=17.8 Hz), 7.09 (d, 1H, J=6.8 Hz), 2.75 (s, 3H). MS (+veelectrospray) 270 (100), (M+).

d) Methyl2-(4-fluorophenyl)-7-methyl-pyrazolo[1,5-a]pyridine-3-carboxylate

To a stirred solution of methyl 3-(4-fluorophenyl)propiolate (3.47 g,19.5 mmol) and 1-amino-2-methylpyridinium2,4,6-trimethylbenzenesulfonate (6.0 g, 19.5 mmol) in dry acetonitrile(75 mL) was added, dropwise over 10 min a solution of1,8-diazabicycloundec-7-ene (5.82 mL, 39 mmol) in dry acetonitrile (25mL). The mixture was allowed to stir at room temperature for about 18hours. The solvent was evaporated under reduced pressure and the residuewas partitioned between water (500 mL) and ethyl acetate (250 mL) andthe organic phase separated. The aqueous was extracted with ethylacetate and the combined organic extracts are dried over anhydrousmagnesium sulfate, and the solvent removed under vacuum. The residue waspurified by chromatography on silica gel using 10:1 hexanes:ethylacetate as eluent to give the title compound as a white solid, 4.65 g(86%). ¹H NMR (CDCl₃) δ 8.15 (d, 1H, J=8.8 Hz), 7.86 (m, 2H), 7.41 (t,₁H, J=8.9 Hz), 7.19 (t, 2H, J=17.6 Hz), 6.87 (d, 1H, J=7.0 Hz), 3.89 (s,3H), 2.85 (s, 3H). MS (+ve ion electrospray) 285 (100), (MH⁺).

e) 1-Amino-2-methylpyridinium 2,4,6-trimethylbenzenesulfonate

To cold (0° C.) trifluoroacetic acid (50 mL) was addedN-tert-butoxycarbonyl-O-(mesitylsulfonyl)hydroxylamine (16.09 g, 51mmol) in portions over about 15 minutes. The solution was then stirredfor about 15 minutes at room temperature. The solution was poured intoice water (250 mL) and the resulting white precipitate was collected byfiltration and air-dried for 5 minutes. The solid was dissolved inchloroform (100 mL) and this solution was dried over anhydrous magnesiumsulfate. The magnesium sulfate was removed by filtration and thefiltrate was added to a solution of 2-picoline (5.0 g, 54 mmol) inchloroform (5 mL). The mixture was stirred for 45 min and then filtered.To the filtrate was added diethyl ether (225 mL) and the product allowedto precipitate. The solid was collected by filtration, washed withdiethyl ether (50 mL) and dried to give the title compound as a whitesolid, 12.9 g (820/%). ¹H NMR (CDCl₃) δ 9.45 (d, 1H), 8.4 (s, 2H), 7.84(t, 1H), 7.55 (t, 1H), 7.50 (d, 1H), 6.80 (s, 2H), 2.81 (s, 3H), 2.62(s, 6H), 2.25 (s, 3H). MS (+ve electrospray) 109 (100), (M⁺).

EXAMPLE 752-(4-Fluorophenyl)-7-methoxy-3-(4-pyridinyl)pyrazolo[1,5-a]-pyridine

In a similar manner as described in Examples 73 and 74, from2-methoxypyridine was obtained the title compound. ¹H NMR (400 MHz,DMSO-d₆) δ 4.12 (s, 3H), 6.52 (d, 1H, J=7.2 Hz), 7.24 (m, 4H), 7.35 (m,2H), 7.51 (dd, 2H, J=5.6 Hz, 8.8 Hz), 8.53 (d, 2H, J=6.0 Hz). MS (ES+)m/320 (M⁺+H).

Alternatively,2-(4-fluorophenyl)-7-methoxy-3-(4-pyridinyl)pyrazolo[1,5-a]-pyridine canbe prepared from7-chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine (seeExample 76) by the following procedure:7-chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]pyridine (0.05g, 0.15 mmol) was added to a solution of sodium methoxide (0.75 mmol) indry methanol (5 mL) and the mixture was heated at reflux for about 24hours. Water was added and the mixture was extracted with ethyl acetate.The combined organic extracts are washed with brine and dried overanhydrous magnesium sulfate. The solution was filtered through a shortpad of silica gel and the solvent was evaporated under vacuum. Theresidue was purified by silica gel chromatography using 1:10 MeOH:Ethylacetate to give the title compound, 0.039 g (80%). ¹H NMR and MS areidentical to those described above.

EXAMPLE 767-Chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-a]-pyridine

A stirred solution of2-(4-fluorophenyl)-3-(4-pyridinyl)-pyrazolo[1,5-a]pyridine (from Example73, 100 mg, 0.346 mmol) in dry tetrahydrofuran (4 mL) was cooled toabout −78° C. under N₂ and n-butyllithium in hexanes (2.5 M in hexanes,0.27 mL, 0.7 mmol) was added dropwise. The mixture was stirred at −78°C. for about 30 min and a solution of p-toluenesulfonyl chloride (0.15g, 0.76 mmol) in dry tetrahydrofuran (1 mL) was added. The mixture wasallowed to warm to room temperature over 30 min and was stirred at roomtemperature for 1 hour. Water was added and the mixture was poured intoa separatory funnel. The organic layer was separated, and the aqueouslayer was extracted with ethyl acetate. The combined organic layers weredried using anhydrous magnesium sulfate, filtered and evaporated.Purification by silica gel chromatography yielded the title compound,0.087 g (78.60/%). ¹H NMR (CDCl₃): δ 8.65 (d, 2H, J=5.8 Hz), 7.55-7.69(m, 3H), 7.30 (d, 2H, J=5.8 Hz), 7.11-7.21 (m, 1H), 7.04-7.13 (m, 3H).MS (ES+ve): 326 (25, M+3), 323 (50, M⁺), 290 (100).

EXAMPLE 772-(4-Fluorophenyl)-3-(2-fluoro-4-pyridinyl)-7-methoxypyrazolo[1,5-a]pyridine

A solution of3-bromo-2-(4-fluorophenyl)-7-methoxypyrazolo[1,5-a]pyridine (fromExample 74, 180 mg, 0.560 mmol), 2-fluoropyridin-4-ylboronic acid (fromExample 80, 112 mg, 0.800 mmol) anddichlorobis(triphenylphosphine)palladium (40.0 mg, 0.056 mmol) inN,N-dimethylformamide (6.00 mL) was placed in a pre-heated oil bath at110° C. To the reaction was added, in a dropwise manner, 2M sodiumcarbonate (0.840 mL, 1.68 mmol). The reaction was allowed to stir forthree hours before cooling to room temperature and filtering through aCelite 545 pad. The Celite filter was washed with ethyl acetate and thefiltrate was concentrated to dryness at 50° C. under vacuum. The residuewas dissolved in methylene chloride and dried over anhydrous magnesiumsulfate. The drying agent was removed by filtration and the filtrate wasconcentrated and purified by silica gel chromatography to yield thetitle compound (110 mg, 0.326 mmol, 580/%). ¹H NMR (CDCl₃): δ 8.14(d,1H, J=5.5 Hz), 7.53(dd, 2H, J=6.0, 8.0 Hz), 7.24-7.32(m, 2H),7.00-7.10(m, 3H), 6.89(s, 1H), 6.23(dd, 1H. J=2.0, 6.0 Hz), 4.2(s, 3H).MS (ES+ve): 338.1 (40, M⁺), 323.1 (100).

EXAMPLE 78N-Butyl-4-[2-(4-fluorophenyl)-7-methoxypyrazolo[1,5-a]pyridin-3-yl]-2-pyridinamine

In a sealed-tube was combined2-(4-Fluorophenyl)-3-(2-fluoro-4-pyridinyl)-7-methoxypyrazolo[1,5-a]pyridine(from Example 77, 20 mg, 0.06 mmol) and n-butylamine (2.0 mL, 1.5 g, 20mmol), and the reaction was placed in a pre-heated oil bath at 130° C.The reaction was stirred at 130° C. until consumption of startingmaterial was indicated by TLC analysis (50% ethyl acetate in hexanes).The contents of the sealed-tube was transferred to a flask andconcentrated to dryness at 50° C. under high vacuum. The residue waspurified by silica gel chromatography to yield the title compound, 2.0mg (0.005 mmol, 8%). ¹H NMR (d₆-acetone): δ 8.04(d, 1H, J=5.1 Hz),7.74(dd, 2H, J=5.7, 9.0 Hz), 7.33-7.38(m, 2H), 7.22(t, 2H, J=9.0 Hz),6.45-6.54(m, 3H), 4.25(s, 3H), 3.30-3.40(m, 2H), 1.60(quint, 2H, J=7.2Hz), 1.45(sext, 2H, J=7.2 Hz), 0.9(t, 3H, J=7.2 Hz). MS (ES+ve): 391.1(100, M⁺), 376.3 (100).

EXAMPLE 79N-{4-[5-Chloro-7-(ethylsulfanyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine

a) 2-(4-Chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone

To a cold (0° C.) solution of 4-chloro-2-picoline (5.0 g, 39 mmol) andethyl 4-fluorobenzoate (6.6 g, 39 mmol) in tetrahydrofuran (100 mL) wasadded lithium bis(trimethylsilyl)amide (80 mL, 1.0 M in tetrahydrofuran,80 mmol) dropwise via a pressure equalizing funnel over 30 minutes. Uponcomplete addition, the cold bath was removed and the resulting solutionwas stirred at room temperature for 15 hours. The reaction mixture wasconcentrated under reduced pressure and methanol was added to thereaction, resulting in the formation of a white precipitate. Theprecipitate was collected by filtration and dried to give2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (9.6 g, 99%) as awhite solid. ¹H-NMR (DMSO-d₆): δ 7.90 (m, 3H), 7.11 (t, 2H), 6.56 (s,1H), 5.67 (s, 1H), 4.14 (m, 2H); ¹⁹F-NMR (DMSO-d₆): δ 115.67; MS m/z 250(M+1).

b) 2-(4-Chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime

To a solution of 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone(9.6 g, 38 mmol) in methanol (200 mL) was added hydroxylaminehydrochloride (13.5 g, 190 mmol) followed by the addition of a sodiumhydroxide solution (7.8 g, 190 mmol in 50 mL of water). The resultingsuspension was heated at reflux for 2 hours and then allowed to cool toroom temperature. The mixture was concentrated and water was added tothe resulting slurry. A white precipitate formed, which was collected byfiltration, washed with water and dried (magnesium sulfate) to give2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (8.45 g,840/%) as a white solid. ¹H-NMR (DMSO-d₆): δ 11.56 (s, 1H), 8.44 (d,1H), 7.80 (m, 2H), 7.40 (m, 2H), 7.22 (m, 2H), 4.29 (s, 2H); ¹⁹F-NMR(DMSO-d₆): 8113.44; MS m/z 265 (M+1).

c) 5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine

To a solution of 2-(4-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanoneoxime (8.0 g, 30 mmol) in 1,2-dimethoxyethane (50 mL) at 0° C. was addedtrifluoroacetic anhydride (6.3 g, 30 mmol), keeping the temperaturebelow 10° C. during the addition. After the addition was complete, thereaction was warmed to room temperature. The solution was then cooled to4° C. and a solution of triethylamine (8.4 mL, 60 mmol) in1,2-dimethoxyethane (20 mL) was added over a period of 0.5 hours. Themixture was allowed to warm to room temperature and was stirred for 1.5hours. To this mixture was added iron(II) chloride (40 mg) and thereaction was heated at 75° C. for 15 hours. The reaction mixture waspoured into water (300 mL). The resulting suspension was extracted withethyl acetate. The combined organics were dried (magnesium sulfate),filtered and concentrated to a solid residue. This residue was purifiedby flash chromatography (1:1 ethyl acetate-hexane) to give5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (4.2 g, 57%) as awhite solid. ¹H-NMR (CDCl₃): δ 8.36 (d, 1H), 7.93 (q, 2H), 7.49 (d, 1H),7.15 (t, 2H), 6.70 (dd, 1H), 6.69 (s, 1H); ¹⁹F-NMR (CDCl₃): δ 113.30; MSm/z 247 (M+1).

d) 5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde

Phosphorous oxychloride (0.6 mL, 6.4 mmol) was added toN,N-dimethylformamide (10 mL) and the resulting mixture stirred at roomtemperature for 10 minutes.5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (1.0 g, 4.1 mmol) wasadded and the reaction mixture was stirred at room temperature for 12hours. The reaction mixture was poured into ice-water and neutralized topH 7 with aquous ammonium hydroxide. The resulting slurry was extractedwith dichloromethane (3×40 mL). The combined organics were washed withbrine, dried (magnesium sulfate), filtered and concentrated to give,after recrystallization from acetonitrile,5-chloro-2-(4-fluorophenyl)pyrazolo [1,5-a]pyridine-3-carbaldehyde (0.95g, 85%) as a white solid. ¹H-NMR (CDCl₃): δ10.07 (s, 1H), 8.49 (d, 1H),8.44 (d, 1H), 7.78 (q, 2H), 7.22 (t, 2H), 7.07 (dd, 1H); MS m/z 275(M+1).

e)1-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-one

To a solution of5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (0.93g, 3.4 mmol) in tetrahydrofuran (20 mL) at −78° C. was addedethynylmagnesium bromide (16 mL, 0.5 M in tetrahydrofuran, 8.0 mmol).The mixture was allowed to warm to room temperature and stirred for 1hour. Water was added to the reaction and the resulting mixture wasextracted with ethyl acetate. The ethyl acetate phase was dried(magnesium sulfate), filtered and concentrated to a solid residue. Thisresidue was dissolved in dichloromethane (50 mL) and manganese dioxide(5 g) was added. This slurry was stirred at room temperature for 2hours. The manganese dioxide was removed by filtration and the filtratewas concentrated to a solid. This solid was purified by flashchromatography (dichloromethane) to give1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-one(0.63 g, 62% for two steps) as a white solid. ¹H-NMR (CDCl₃): δ 8.52 (d,1H), 8.47 (d, 1H), 7.69 (q, 2H), 7.18 (t, 2H), 7.07 (dd, 1H), 3.00 (s,1H); ¹⁹F-NMR (CDCl₃): δ 111.69; MS m/z 299 (M+1).

f)4-[5-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

To a solution of 1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-butyn-1-one (0.61 g, 2.0 mmol) inN,N-dimethylformamide was added cyclopentyl guanidine hydrochloride(0.67 g, 4.1 mmol) followed by anhydrous potassium carbonate (0.57 g,4.1 mmol). The resulting mixture was heated at 80° C. for 12 hours. Uponcooling to room temperature, water was added. The mixture was extractedwith ethyl acetate. The ethyl acetate phase was washed with brine, dried(magnesium sulfate), filtered and concentrated in vacuo. The resultingresidue was purified by flash chromatography (1:1 ethyl acetate-hexane)to give, after recrystallization from acetonitrile,4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(0.6 g, 74%) as a white solid. ¹H-NMR (CDCl₃): 68.54 (broad s, 1H), 8.40(d, 1H), 8.04 (d, 1H), 7.60 (q, 2H), 7.16 (t, 2H), 6.88 (dd, 1H), 6.28(d, 1H), 5.22 (d, 1H), 4.40 (m, 1H), 1.4-2.2 (m, 8H); ¹⁹F-NMR (CDCl₃): δ112.5; MS m/z 408 (M+1).

g)N-{4-[5-Chloro-7-(ethylsulfanyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine

To a solution of4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(150 mg, 0.37 mmol) in anhydrous tetrahydrofuran (5 mL) at −78° C. wasadded n-butyllithium (0.7 mL, 1.1 mmol of 1.6 M solution in hexane). Theresulting solution was stirred for 10 minutes at −78° C., followed byaddition of diethyldisulfide (0.14 mL, 1.1 mmol). The reaction wasstirred at −78° C. for 20 minutes and then allowed to warm to roomtemperature. Water and ethyl acetate were added to the reaction mixture.The phases were separated, the aqueous phase washed with ethyl acetateand the combined organic phase dried (magnesium sulfate), filtered andconcentrated in vacuo. The resulting solid was purified by flashchromatography (1:1 ethyl acetate-hexane) to give, afterrecrystallization from ethyl acetateN-{4-[5-chloro-7-(ethylsulfanyl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinyl}-N-cyclopentylamine(90 mg, 52%) as a solid. ¹H-NMR (CDCl₃): δ 8.42(broad s, 1H), 8.08 (d,1H), 7.66 (q, 2H), 7.17 (t, 2H), 6.73 (d, 1H), 6.31 (d, 1H), 5.18 (d,1H), 4.20 (m, 1H), 3.22 (q, 2H), 2.0-2.1 (m, 2H), 1.4-1.9 (m, 9H);¹⁹F-NMR (CDCl₃): δ 112.8; MS m/z 468 (M+1).

EXAMPLE 80 2-Fluoropyridin-4-ylboronic Acid

To a stirred solution of n-butyl lithium (3.2 mL, 2.5M, 8.0 mmol) in drydiethyl ether (20 mL) at −78° C. was added a solution of2-fluoro-4-iodopyridine (1.5 g, 6.7 mmol) in dry ether (10 mL) and thereaction mixture was stirred at −78° C. for 10 minutes. Tributyl borate(2.4 mL, 2.01 g, 8.7 mmol) was added and the reaction mixture wasallowed to stir to room temperature over 2 hours. Water (5 mL) was addedfollowed by 2N aqueous sodium hydroxide solution (10 mL) to sissolve thesolids. The organic phase was separated. The aqueous phase was acidifiedto pH3 using 6N HCl and the resulting white solid was collected byfiltration and dried under vacuum to give the title compound, 0.74 g(78%). ¹H NMR (DMSO-d6) δ 8.65 (s, 2H), 8.21 (d, 1H, J=4.8 Hz), 7.59 (t,1H, J=4.8 Hz), 7.37 (d, 1H, J=1.8 Hz).

EXAMPLE 81 Ethyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylate

a) 1-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone

To a solution of 4-fluoroacetophenone (13.8 g, 0.100 mol) and2-chloro-5-trifluoromethylpyridine (20.0 g, 0.110 mol) intetrahydrofuran (400 mL) was added sodium hydride (95%, 5.56 g, 0.220mol) in several portions. The reaction was stirred at room temperaturefor 72 hours then carefully quenched by the addition of water (300 mL)and diethyl ether (200 mL). The organic layer was separated andextracted with 6N HCl (2×300 mL). The aqueous extracts were cooled to 0°C. and 6N NaOH was used to adjust the solution to pH12. The mixture wasthen extracted with diethyl ether and the combined organic extracts weredried over magnesium sulfate. The drying agent was removed by filtrationand the filtrate was evaporated to dryness to afford the title compoundas a tautomeric mixture, 20.9 g (73%). ¹H NMR (CDCl₃): δ 8.87(s),8.63(s), 8.14(dd, J=5.1, 8.4 Hz), 8.00-7.83(m), 7.51(d, J=8.4 Hz),7.22-7.12(m), 6.13(s), 4.60(s). MS (ES): 284 (M+1).

b) 1-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone Oxime

To a solution of1-(4-fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone (80.0 g,0.282 mol) in methanol (1 L) at room temperature was added 10% aqueoussodium hydroxide (436 mL, 1.09 mol). The resulting solution was stirredvigorously as solid hydroxylamine hydrochloride (98.0 g, 1.40 mol) wasadded. The mixture was heated to reflux for 2 hours, treated withdecolorizing charcoal while hot, then filtered through Celite while hot.The filtrate was concentrated to one-half its original volume and thencooled to 0° C. with stirring for one hour. The resulting solids werecollected by filtration, washed with water, and dried under vacuum at50° C. overnight to provide the title compound as a light yellow powder,73.9 g (88%). ¹H NMR (DMSO-d6): δ 11.60(s, 1H), 8.86(s, 1H), 8.14(dd,1H, J=2.1, 8.1 Hz), 7.78(dd, 2H, J=5.7, 9.0 Hz), 7.53(d, 1H, J=8.4 Hz),7.23(t, 2H, J=9.0 Hz), 4.40(s, 2H). MS (ES): 299 (M+1).

c) 3-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)-2H-azirine

To a solution of1-(4-fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone oxime (25.0g, 0.084 mol) in methylene chloride (400 mL) was added triethylamine(46.7 mL, 0.335 mol). The solution was cooled to 0° C. under a nitrogenatmosphere, and trifluoroacetic anhydride (14.1 mL, 0.100 mol) was addeddropwise. The reaction was stirred for 0.5 hours then quenched withwater. The organic layer was separated and dried over anhydrousmagnesium sulfate. The drying agent was removed by filtration and thesolvent was evaporated from the filtrate to leave an oil. The residuewas loaded onto a silica gel column and eluted with 15% ethyl acetate inhexanes to give the title compound as an oil which solidified onstanding, 19.4 g (82%). ¹H NMR (CDCl₃): δ 8.76(s, 1H), 7.93(dd, 2H,J=5.4, 8.7 Hz), 7.83(dd, 1H. J=2.1, 8.4 Hz), 7.27(t, 2H, J=8.7 Hz),7.21(d, 1H, J=8.1 Hz), 3.54(s, 1H). MS (ES): 281 (M+1).

d) 2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine

3-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)-2H-azirine (40.0 g,0.143 mol) was dissolved in 1,2,4-trichlorobenzene (400 mL) and themixture was heated to 200° C. for 10 hours. The reaction mixture wasthen cooled to room temperature and poured onto a silica gel column. Thecolumn was eluted with hexanes to remove the 1,2,4-trichlorobenzene, andthen with 20% diethyl ether in hexanes to elute the product. The desiredfractions were combined and the solvent was evaporated under reducedpressure to leave the title compound, 28.7 g (71%). ¹H NMR (CDCl₃): δ8.84(s, 1H), 7.98(dd, 2H, J=5.4, 8.7 Hz), 7.65(d, 1H, J=9.3 Hz), 7.28(d,1H, J=9.3 Hz), 7.20(t, 2H, J=8.7 Hz), 6.88(s, 1H). MS (ES): 281 (M+1).

e)2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde

To a cold (0° C.) solution of phosphorus oxychloride (8.0 mL, 86 mmol)in N,N-dimethylformamide (160 mL) was added2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo-[1,5-a]pyridine (11.0 g,39.3 mmol). The reaction mixture was stirred at room temperature for 72hours, then quenched with ice water. The solid precipitate was collectedon a filter to provide2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde(11.4 g, 94%) as a white solid. R_(f) 0.45 (4:1 hexanes:ethyl acetate);¹H NMR (400 MHz, CDCl₃) δ 10.15 (s, 1H), 8.92 (s, 1H), 8.53 (d, 1H),7.80 (m, 2H), 7.70 (d, 1H), 7.27 (t, 2H); ¹⁹F NMR (CDCl₃) δ −62.62,−110.62; MS m/z 307 (M−1).

f)1-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol

To a cold (−78° C.) suspension of2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde(11.4 g, 37.0 mmol) in tetrahydrofuran (100 mL) was addedethynylmagnesium bromide (111 mL, 0.5 M in tetrahydrofuran, 56 mmol).The reaction mixture was warmed to room temperature and stirred for 14hours. The reaction mixture was poured into water and adjusted toneutral pH with 1N aqueous hydrochloric acid. The aqueous mixture wasextracted with ethyl acetate. The combined extracts were washed withwater and brine. The organic layer was dried over magnesium sulfate.Filtration and concentration provided 1-[2-(4-fluorophenyl)6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol (11.9 g,96%) as a tan solid. R_(f) 0.18 (4:1 hexanes:ethyl acetate); ¹H NMR (300MHz, CDCl₃) δ 8.81 (s, 1H), 8.15 (d, 1H), 7.75 (m, 2H), 7.35 (d, 1H),7.19 (t, 2H), 5.76 (s, 1H), 2.71 (d, 1H), 2.60 (d, 1H); MS m/z 335(M+1).

g)1-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one

To a cold (0° C.) solution of1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(5.00 g, 15.0 mmol) in chloroform (400 mL) was added manganese dioxide(130 g, 1.50 mol). The reaction mixture was stirred at 0° C. for 1.5hours. The reaction mixture was filtered through a pad of Celite. Thefiltrate was concentrated in vacuo to provide1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo-[1,5-a]pyridin-3-yl]-2-propyn-1-one(3.44 g, 69%) as a clear oil. R_(f) 0.39 (4:1 hexanes:ethyl acetate); ¹HNMR (400 MHz, CDCl₃) δ 8.90 (s, 1H), 8.61 (d, 1H), 7.72-7.69 (m, 3H),7.17 (m, 2H), 3.06 (s, 1H); MS m/z 333 (M+1).

h)N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

To a suspension of N-cyclopentylguanidine hydrochloride (2.20 g, 13.5mmol) in ethanol (70 mL) was added sodium ethoxide (4.5 mL, 3 M inethanol, 14 mmol). The mixture was stirred at room temperature for 30minutes, then cooled to 0° C. To this mixture was added1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(3.44 g, 10.4 mmol) portionwise. The reaction mixture was stirred at 0°C. for 30 minutes, followed by room temperature for 15 hours. Thereaction mixture was diluted with water (400 mL). The solid precipitatewas collected on a filter to provideN-cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(4.48 g, 98%) as an orange solid. ¹H NMR (400 MHz, CDCl₃) δ 8.84 (s,1H), 8.51 (d, 1H), 8.11 (d, 1H), 7.64 (dd, 2H), 7.44 (dd, 1H), 7.17 (t,2H), 6.33 (d, 1H), 5.17 (d, 1H), 4.34 (m, 1H), 2.15-2.06 (m, 2H),1.84-1.52 (m, 6H); ¹⁹F NMR (CDCl₃): δ −62.70, −112.25 MS m/z 442 (M+1);mp 155-156° C.

Alternatively,N-cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinaminefrom 2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine maybe synthisized through the following steps.

aa)1-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone

To a mixture of2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine (10.30 g,36.76 mmol) and acetic anhydride (100 mL) was added conc. sulfuric acid(10 drops) and the mixture was stirred and heated at reflux for 1 hour.The reaction mixture was cooled to room temperature and poured into icewater (300 mL). 2N Aqueous sodium hydroxide solution was added to raisethe pH of the solution to about 10 and the resulting orange precipitatewas collected by filtration. The solid was washed with water, air-dried,and then dried under vacuum to afford the title compound as an orangesolid, 11.87 g (quant.). ¹H NMR (DMSO-d₆): δ 9.58 (s, 1H), 8.41 (d, 1H,J=9.3 Hz), 7.89 (d, 1H, J=9.5 Hz), 7.74 (m, 2H), 7.39 (m, 2H), 2.22 (s,3H). MS (ES) 323 (M+1).

bb)(2E)-3-(Dimethylamino)-1-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo-[1,5-a]pyridin-3-yl]-2-propen-1-one

A mixture of1-[2-(4-Fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone(11.85 g), 36.77 mmol) and N,N-dimethylformamide dimethyl acetal (100mL) was stirred at reflux for 17 hours. The mixture was cooled to roomtemperature and then to 0° C. The resulting orange precipitate wascollected by filtration, washed with cold hexanes, and dried undervacuum to afford the title compound as an orange solid, 10.17 g (730/%).¹H NMR (DMSO-d₆): δ 9.44 (s, 1H), 8.22 (d, 1H, J=9.4 Hz), 7.75 (m, 2H),7.65 (d, 1H, J=9.5 Hz), 7.56 (d, 1H, J=12.4 Hz), 7.35 (m, 2H), 5.05 (d,1H, J=12.3 Hz), 3.04 (s, 3H), 2.56 (s, 3H). MS (+ve ion electrospray)377 (80), (M⁺).

cc)N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

To a solution of(2E)-3-(dimethylamino)-1-[2-(4-fluorophenyl)-6-(trifluoromethyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-propen-1-one(314 mg, 0.83 mmol)) in 1-methyl-2-pyrrolidinone (3 mL) was addedN-cyclopentylguanidine hydrochloride (271 mg, 1.66 mmol) and potassiumcarbonate (229 mg, 1.66 mmol). The mixture was heated at 140° C. for 8hours. Upon cooling to room temperature, ether was added followed bywater. The organics were washed with brine, and the aqueous layer wasextracted with ether. The combined organics were dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified byflash chromatography on silica (4:1 hexanes-ethyl acetate) to giveN-cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(204 mg, 56%) as a white solid. ¹H NMR (CDCl₃): δ 8.84 (s, 1H), 8.51 (d,1H), 8.11 (d, 1H), 7.64 (dd, 2H), 7.44 (dd, 1H), 7.17 (t, 2H), 6.33 (d,1H), 5.17 (d, 1H), 4.34 (m, 1H), 2.15-2.06 (m, 2H), 1.84-1.52 (m, 6H);¹⁹F NMR (CDCl₃): δ −62.70, −112.25; MS m/z 442 (M+1); mp 155-156° C.

i)N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

To a dry round bottom flask was added sodium metal (1.9 g, 83 mmol).Ethanol (110 mL) was added and allowed to react with sodium at roomtemperature until completely dissolved.N-Cyclopentyl-4-[2-(4-fluorophenyl)-6-(trifluoromethyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(4.48 g, 10.1 mmol) was added and the reaction mixture was stirred at60° C. for 18 hours. The reaction mixture was cooled and concentrated invacuo to approximately one-fourth of the original volume. The resultingmixture was diluted with water and extracted with ethyl acetate. Theorganic layer was washed with water and brine, then dried over magnesiumsulfate. Filtration and concentration providedN-cyclopentyl-4-[2-(4-fluorophenyl)-6-(triethoxymethyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(4.86 g, 92%) as an off-white solid. R_(f) 0.15 (4:1 hexanes:ethylacetate); ¹H NMR (300 MHz, CDCl₃) δ 8.81 (s, 1H), 8.39 (d, 1H), 8.06 (d,1H), 7.62 (m, 2H), 7.47 (d, 1H), 7.14 (t, 2H), 6.32 (d, 1H), 5.12 (d,1H), 4.35 (m, 1H), 3.43 (q, 6H), 2.08 (m, 2H), 1.80-1.51 (m, 6H), 1.21(t, 9H); MS m/z 520 (M+1).

j)4-[7-Chloro-2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

To a cold (0° C.) solution of diisopropylamine (4.1 mL, 29 mmol) intetrahydrofuran (25 mL) was added butyllithium (17 mL, 1.6 M in hexanes,28 mmol) dropwise. The resultant solution was stirred at 0° C. for 10minutes then cooled to −78° C. The reaction mixture was transferred viasyringe to a cold (−78° C.) solution ofN-cyclopentyl-4-[2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(4.86 g, 9.35 mmol) in tetrahydrofuran (25 mL). The reaction mixture wasstirred at −78° C. for 30 minutes. Carbon tetrachloride (3.6 mL 37 mmol)was added and the resulting mixture was warmed to room temperature andstirred for 2 hours. The reaction mixture was poured onto ice. After theice had melted, the aqueous mixture was extracted with ethyl acetate.The organic layer was washed with water and brine, then dried oversodium sulfate. Filtration and concentration followed by flashchromatography (4:1 hexanes:ethyl acetate) provided4-[7-chloro-2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(2.37 g, 46%) as a yellow solid. R_(f) 0.36 (4:1 hexanes:ethyl acetate);¹H NMR (400 MHz, CDCl₃) δ 8.36 (d, 1H), 8.08 (d, 1H), 7.85 (d, 1H), 7.67(m, 2H), 7.15 (t, 2H), 6.33 (d, 1H), 5.15 (d, 1H), 4.36 (m, 1H), 3.46(q, 6H), 2.10 (m, 2H), 1.81-1.53 (m, 6H), 1.26 (t, 9H); MS m/554 (M+1).

k) Ethyl7-chloro-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridine-6-carboxylate

To a solution of4-[7-chloro-2-(4-fluorophenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine(375 mg, 0.677 mmol) in acetone (8 mL) and water (2 mL) was addedp-toluenesulfonic acid monohydrate (321 mg, 1.69 mmol). The reactionmixture was stirred at room temperature for 2 hours, then quenched withice water. The reaction mixture was neutralized with saturated aqueoussodium bicarbonate solution, then concentrated in vacuo to remove themajority of the acetone. The resultant mixture was extracted with ethylacetate. The organic layer was washed with water and brine, then driedover magnesium sulfate. Filtration and concentration, followed by flashchromatography (29:1 dichloromethane:methanol) provided ethyl7-chloro-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carboxylate(175 mg, 540/%) as a brown solid. R_(f) 0.08 (29:1dichloromethane:methanol); ¹H NMR (400 MHz, CDCl₃) δ 8.36 (d, 1H), 8.09(d, 1H), 7.82 (d, 1H), 7.65 (m, 2H), 7.14 (t, 2H), 6.30 (d, 1H), 5.19(d, 1H), 4.46 (q, 2H), 4.32 (m, 1H), 2.06 (m, 2H), 1.77-1.21 (m, 9H); MSm/z 480 (M+1).

l) Ethyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylate

To a solution of ethyl7-chloro-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carboxylate(90 mg, 0.19 mmol) in tetrahydrofuran (1 mL) was added dimethylzinc (281μL, 2.0 M in toluene, 0.56 mmol) andtetrakis(triphenylphosphine)palladium (21 mg, 0.018 mmol). The reactionmixture was stirred at 60° C. for 16 hours. The reaction mixture wasquenched with ice water then extracted with ethyl acetate. The organiclayer was washed with water and brine, then dried over magnesiumsulfate. Filtration and concentration, followed by flash chromatography(49:1 dichloromethane:methanol) provided ethyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylate(40 mg, 45%). ¹H NMR (300 MHz, CDCl₃) δ 8.34 (d, 1H), 8.11 (d, 1H), 7.91(d, 1H), 7.70 (m, 2H), 7.19 (t, 2H), 6.36 (d, 1H), 5.33 (br, 1H), 4.47(q, 2H), 4.38 (m, 1H), 3.26 (s, 3H), 2.12 (m, 2H), 1.83-1.43 (m, 9H); MSm/z 460 (M+1).

EXAMPLE 823-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylicAcid

To a solution of ethyl3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylate(40 mg, 0.087 mmol) in dioxane (600 μL) was added lithium hydroxide (300μL, 1M aqueous, 0.30 mmol). The reaction mixture was stirred at roomtemperature 16 hours. The reaction mixture was concentrated in vacuo toremove dioxane, then diluted with water. The aqueous mixture wasacidified with 1 N aqueous hydrochloric acid. Upon standing for 72hours, a solid precipitate had formed which was collected by filtrationto provide3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylicacid (31 mg, 82%). R_(f) 0.10 (19:1 dichloromethane:methanol); MS m/z432 (M+1).

EXAMPLE 833-[2-(Cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxamide

Thionyl chloride (200 μL, 2.7 mmol) was added to3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxylicacid (31 mg, 0.072 mmol) which had been pre-cooled to 0° C. The reactionmixture was stirred at room temperature for 1 hour. The excess thionylchloride was removed in vacuo. To a solution of the residue indichloromethane (300 μL) was added cyclopropylamine (50 uL, 0.72 mmol).The reaction mixture was stirred at room temperature for 30 minutes. Theresultant mixture was quenched with water and diluted with ethylacetate. Saturated aqueous sodium bicarbonate solution was added to thebiphasic mixture. The organic layer was washed with water and brine,then dried over magnesium sulfate. Filtration and concentration,followed by flash chromatography (3:2 hexanes:ethyl acetate to 2:3hexanes:ethyl acetate) provided3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-cyclopropyl-2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridine-6-carboxamide(15 mg, 44%) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (d,1H), 8.05 (d, 1H), 7.62 (m, 2H), 7.30 (d, 1H), 7.13 (t, 2H), 6.29 (d,1H), 5.10 (d, 1H), 4.30 (m, 1H), 2.96 (s 3H), 2.94 (m, 1H), 2.05 (m,2H), 1.76-1.50 (m, 6H), 0.92 (m, 2H), 0.66 (m, 2H); MS m/z 471 (M+1).

EXAMPLE 84N-Butyl-4-[7-butyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

a) 2-(6-Chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone

To a cold (0° C.) solution of 6-chloro-2-picoline (21.4 mL, 196.0 mmol)and ethyl 4-fluorobenzoate (57.5 mL, 391.2 mmol) in tetrahydrofuran (311mL) was added lithium bis(trimethylsilyl)amide (391 mL, 1.0 M intetrahydrofuran, 391.0 mmol) dropwise via a pressure equalizing funnelover 1 hour. Upon complete addition, the cold bath was removed and theresultant solution was heated to 45° C. for 15 hours. The mixture wascooled to room temperature and quenched by the addition of water. Etherwas added and the organic layer was washed with brine. The aqueous layerwas extracted with ether and the combined organics were dried overmagnesium sulfate. Filtration and concentration gave a solid residuewhich was purified by recrystallization from ethyl acetate-hexanes toprovide 2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone (32.2 g,66%) as a tinted off-white solid existing as a keto-enol tautomericmixture. ¹H NMR (CDCl₃): for the keto tautomer δ 8.11 (m, 2H), 7.66 (t,1H), 7.30-7.25 (m 2H), 7.17 (t, 2H), 4.48 (s 2H), ¹F NMR (CDCl₃) δ−104.72 (keto), −111.64 (enol); MS m/z 250 (M+1).

b) 2-(6-Chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone Oxime

To a solution of 2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone(74.9 g, 299.8 mmol) in methanol (900 mL) was added hydroxylaminehydrochloride (104 g, 1.49 mol) followed by sodium hydroxide (600 mL,10% aqueous, 1.5 mol). The resultant suspension was heated to reflux for2 hours and then cooled to room temperature. The mixture wasconcentrated in vacuo and the residue taken up in ether and water. Theorganic layer was washed with brine. The aqueous layer was extractedwith ether and the combined organics were dried over magnesium sulfate.Filtration and concentration gave a solid residue which was purified byrecrystallization from ethyl acetate-hexa nes to provide2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone oxime (67.9 g, 86%)as a white solid. ¹H NMR (CDCl₃): δ 8.69 (s, 1H), 7.71 (dd, 2H), 7.53(t, 1H), 7.18-7.16 (m, 2H), 7.03 (t, 2H), 4.37 (s, 2H); ¹⁹F NMR (CDCl₃)δ −111.77; MS m/z 265 (M+1).

c) 7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine

To a solution of 2-(6-chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanoneoxime (109.2 g, 414 mmol) in 1,2-dimethoxyethane. (500 mL) at 0° C. wasadded trifluoroacetic anhydride (59 mL, 414 mmol), keeping thetemperature below 10° C. After the addition was complete, the reactionwas warmed to 15° C. The solution was then cooled to 4° C. and asolution of triethylamine (116 mL, 828 mmol) in 1,2-dimethoxyethane (60mL) was added over 0.5 hours. After warming to room temperature, themixture was stirred for 1.5 hours. To this was added iron(II) chloride(0.52 g, 4.1 mmol) and the reaction was heated to reflux for 3 hours.The reaction was concentrated and the resulting solid was recrystallizedfrom ethyl acetate-hexanes to give7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (69.7 g, 68%) asoff-white needles. ¹H NMR (CDCl₃): δ 8.03 (m, 2H), 7.54 (d, 1H), 7.16(m, 3H), 6.93 (d, 1H), 6.91 (s, 1H); MS m/z 247 (M+1); mp 156-157° C.

d) 7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde

N,N-Dimethylformamide (100 mL) was cooled to 0° C. and treated withphosphorous oxychloride (5.7 mL, 60.8 mmol). After the addition wascomplete, the mixture was warmed to room temperature and stirred for 1hour. To this was added7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine (10.0 g, 40.5 mmol)and the resultant solution was stirred overnight. Water was added,followed by dichloromethane. The aqueous layer was extracted withdichloromethane. The combined organics were washed with brine, driedover magnesium sulfate, filtered and concentrated. The residue wasrecrystallized from diethyl ether and hexanes to give7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (10.6g, 95%) as a fluffy white solid. ¹H NMR (CDCl₃): δ 10.07 (s, 1H), 8.37(d, 1H), 7.78 (m, 2H), 7.48 (t, 1H), 7.20 (m, 3H); ¹⁹F NMR (CDCl₃)8-111.25; MS m/z 275 (M+1); Anal. Calcd for C₁₄H₈ClFN₂O: C, 61.22; H,2.94; N, 10.20. Found: C, 61.34; H, 2.90; N, 10.15. mp 212-213° C.(decomp.).

e)1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol

In a similar manner as described in Example 81 from7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (5.49g, 20.0 mmol) and ethynylmagnesium bromide (100 mL 0.5 M intetrahydrofuran, 50.0 mmol) at 0° C., recrystallized fromdichloromethane, was obtained1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(5.3 g, 88%) as a pale yellow crystalline solid. ¹H NMR (CDCl₃): δ 8.04(d, 1H), 7.79 (m, 2H), 7.20 (m, 3H), 7.01 (d, 1H), 5.77 (m, 1H), 2.69(d, 1H), 2.32 (d, 1H); MS m/z 301 (M+1).

f)1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one

In a similar manner as described in Example 81, from1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-ol(5.30 g, 17.6 mmol) was obtained1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(4.04 g, 77%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.45 (d, 1H), 7.67(m, 2H), 7.50 (t, 1H), 7.19 (d, 1H), 7.12 (t, 2H), 2.93 (s, 1H); MS m/z299 (M+1).

g)N-Butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

In a similar manner as described in Example 81 from1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(0.50 g, 1.7 mmol), N-butylguanidine sulfate and sodium ethoxide (0.81mL, 21 wt % in ethanol, 2.2 mmol) at room temperature was obtainedN-butyl-4-[7-chloro-2-(4-fluorophenyl)-pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(0.39 g, 590/%) as a fluffy pale yellow solid. ¹H NMR (CDCl₃): δ 8.40(d, 1H), 8.07 (d, 1H), 7.65 (m, 2H), 7.29 (m, 1H), 7.15 (t, 2H), 7.06(d, 1H), 6.32 (d, 1H), 5.16 (broad s, 1H), 3.49 (q, 2H), 1.71-1.41 (m,4H), 0.99 (t, 3H); ¹⁹F NMR (CDCl₃) δ −112.77, MS m/z 396 (M+1).

h)N-Butyl-4-[7-butyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

To a cold (−78° C.) solution of 9-methoxy-9-borabicyclo[3.3.1]nonane(1.1 mL, 1.0 M in hexane, 1.1 mmol) in tetrahydrofuran was addedn-butyllithium (696 μL, 1.6 M in hexane, 1.1 mmol) dropwise. Theresultant mixture was warmed to room temperature, then potassiumphosphate (371 μL 3.0 M aqueous, 1.1 mmol) was added. A solution ofN-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(44 mg, 0.11 mmol) and[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (9 mg,complex with dichloromethane, 0.011 mmol) in N,N-dimethylformamide (1.5mL) was added to the stirring borane solution. The reaction mixture wasstirred 16 hours at room temperature. The resultant mixture was dilutedwith ethyl acetate, washed with water and brine, then dried overmagnesium sulfate. Filtration and concentration, followed by flashchromatography (4:1 hexanes:ethylacetate) provided a crude residue. To asolution of the crude residue in dioxane (10 mL) was added saturatedaqueous sodium acetate solution (1 mL) and 30% aqueous hygrogen peroxide(1 mL). After stirring at room temperature for 2 hours, the mixture wasdiluted with ethyl acetate, washed with water and brine, then dried overmagnesium sulfate. Filtration and concentration, followed by flashchromatography (59:1 dichloromethane:methanol) providedN-butyl-4-[7-butyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(7 mg, 16%). ¹H NMR (400 MHz, CDCl₃) δ 8.29 (d, 1H), 8.05 (d, 1H), 7.66(m, 2H), 7.29 (m, 1H), 7.14 (t, 2H), 6.77 (d, 1H), 6.33 (d, 1H), 5.17(br, 1H), 3.49 (m, 2H), 3.22 (t, 2H), 1.87 (m, 2H), 1.69-1.42 (m, 6H),1.02-0.97 (m, 6H); MS m/z 418 (M+1). To a solution of the product inether was added 1 M HCl in ether. The precipitated solid was isolated togive the corresponding hydrochloride salt as a pale yellow solid.

EXAMPLE 85N-Butyl-4-[2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

To a solution ofN-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(80 mg, 0.20 mmol) in tetrahydrofuran (1 mL) was added dimethylzinc (304μL, 2.0 M in toluene, 0.60 mmol) andtetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol). Thereaction mixture was heated at 60° C. for 16 hours. The reaction mixturewas cooled, then quenched with ice water. The resultant mixture wasextracted with ethyl acetate. The organic layer was washed with waterand brine, then dried over magnesium sulfate. Filtration andconcentration, followed by flash chromatography (3:1 hexanes:ethylacetate) providedN-butyl-4-[2-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(24 mg, 32%) as a yellow solid. R_(f) 0.33 (2:1 hexanes:ethyl acetate);¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, 1H), 8.04 (d, 1H), 7.64 (m, 2H), 7.27(m, 1H), 7.13 (t, 2H), 6.77 (d, 1H), 6.31 (d, 1H), 5.17 (br, 1H), 3.48(m, 2H), 2.80 (s, 3H), 1.65 (m, 2H), 1.45 (m, 2H), 0.97 (t, 3H); MS m/z376 (M+1).

EXAMPLE 86N-Butyl-4-[2-(4-fluorophenyl)-7-octylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

A mixture of 9-borabicyclo[3.3.1]nonane dimer (32 mg, 0.13 mmol) andtetrahydrofuran was stirred at room temperature for 2 hours. To theresultant solution was added 1-octene (38 μL 0.24 mmol) and the reactionmixture was stirred 4 hours at room temperature. Potassium phosphate(169 μL, 3 M aqueous, 0.507 mmol) was added and the reaction was stirredfor 15 minutes. A solution ofN-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(80 mg, 0.20 mmol) and[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (8 mg, 0.01mmol) in N,N-dimethylformamide was added to the borane solution andstirred 18 hours. In a separate flask, 9-borabicyclo[3.3.1]nonane dimer(32 mg, 0.13 mmol) was stirred with tetrahydrofuran for 2 hours, towhich 1-octene (38 μL, 0.24 mmol) was added and stirred 4 hours.Potassium phosphate (169 μL, 3 M aqueous, 0.507 mmol) was added and thesolution was stirred for 15 minutes. This fresh borane solution wasadded to the original reaction mixture. Additional[1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (8 mg, 0.01mmol) was added and the reaction mixture was stirred 24 hours at roomtemperature. The reaction mixture was diluted with ethyl acetate. Theorganic layer was washed with water and brine, then dried over magnesiumsulfate. Filtration and concentration, followed by flash chromatography(39:1 dichloromethane:methanol) providedN-butyl-4-[2-(4-fluorophenyl)-7-octylpyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(8 mg, 8%). ¹H NMR (300 MHz, CD₃OD) δ 8.80-8.55 (br, 1H), 7.84 (br, 1H),7.71-7.65 (m, 3H), 7.35 (t, 2H), 7.17 (d, 1H), 6.55 (br, 1H), 3.32 (m,2H), 3.26 (t, 2H), 1.90 (m, 2H), 1.75 (m, 2H), 1.54-1.25 (m, 12H), 1.03(t, 3H), 0.89 (t, 3H); MS m/z 474 (M+1).

EXAMPLE 87N-Cyclopropyl-4-[7-ethyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

a) 4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine

In a similar manner as described in Example 84, from1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one(2.65 g, 8.9 mmol) and N-cyclopropylguanidine sulfate (2.27 g, 11.5mmol) was prepared4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine(1.59 g, 47%) as a yellow solid. ¹H NMR (CDCl₃): δ 8.66 (m, 1H), 8.03(m, 1H), 7.66 (m, 2H), 7.35 (t, 1H), 7.18 (m, 3H), 6.40 (d, 1H), 6.06(broad, 1H), 2.90 (m, 1H), 0.91 (m, 2H), 0.70 (m, 2H); ¹⁹F NMR (CDCl₃) δ−112.22; MS m/z 380 (M+1).

b)N-Cyclopropyl-4-[7-ethyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine

In a similar manner as described in Example 85, from4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropyl-2-pyrimidinamine.(100 mg, 0.26 mmol) and diethylzinc was preparedN-cyclopropyl-4-[7-ethyl-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-pyrimidinamine(51.6 mg, 52%) as an off-white solid. ¹H NMR (CDCl₃): δ 8.51 (m, 1H),7.99 (m, 1H), 7.63 (m, 2H), 7.35 (m, 1H), 7.16 (t, 2H), 6.82 (d, 1H),6.37 (d, 1H), 3.25 (q, 2H), 2.87 (m, 1H), 1.45 (t, 3H), 0.88 (m, 2H),0.67 (m, 2H); ¹⁹F NMR (CDCl₃) δ −113.32; MS m/z 374 (M+1).

EXAMPLE 88 Dimethyl2-(4-fluorophenyl)-3-(4-(2-cyclopropylamino)pyrimidinyl)-7-pyrazolo[1,5-a]pyridinylcarboxamide

To a stirred solution of 2-(4-fluorophenyl)-7-pyrazolo[1,5-a]pyridine(5.38 g, 25 mmol) in dry tetrahydrofuran (100 mL) at −78° C. was addedn-butyl lithium (2.5 M in hexanes. 12.2 mL, 30 mmol) and the mixture wasstirred for 20 min. Dimethyl carbamoyl chloride (7.0 mL, 76 mmol) wasadded in one portion and the mixture was allowed to warm to roomtemperature. Diethyl ether was added followed by saturated aqueoussodium bicarbonate solution. The organic phase was separated and driedusing anhydrous sodium sulfate. The drying agent was removed byfiltration and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel chromatography to give dimethyl2-(4-fluorophenyl)-7-pyrazolo[1,5-a]pyridinylcarboxamide as a lightgreen solid, 6.07 g (85%). In a similar manner as described in Example81 from dimethyl2-(4-fluorophenyl)-7-pyrazolo[1,5-a]pyridinylcarboxamide was obtainedthe title compound. ¹H NMR (DMSO-d₆): δ 8.71 (d, 1H, J=8.1 Hz), 8.11 (d,1H, J=5.1 Hz), 7.65 (m, 2H), 7.57 (dd, 1H, J=7.2, 8.7 Hz), 7.44 (d, 1H,J=2.7 Hz), 7.37 (m, 2H), 7.18 (d, 1H, J=6.3 Hz), 6.26 (d, 1H, J=5.1 Hz),3.11 (s, 3H), 2.84 (s, 3H), 2.65 (m, 1H), 0.74 (m, 2H), 0.55 (m, 2H). MS(ES+ve): 417 (87%, M⁺).

EXAMPLE 89N-Cyclopentyl-4-[2-(4-fluorophenyl)-5-morpholin-4-ylpyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine

In a similar manner as described for above examples the title compoundwas prepared as a solid. ¹H NMR (CDCl₃): δ 8.32 (d, 1H), 8.00 (d, 1H),7.73 (s, 1H), 7.63 (q, 2H), 7.15 (t, 2H), 6.66 (dd, 1H), 6.25 (d, 1H),5.35 (m, 1H), 4.45 (m, 1H), 3.90 (m, 4H), 3.30 (m, 4H), 2.1-2.0 (m, 2H),1.9-1.5 (m, 6H); ¹⁹F NMR (CDCl₃): δ −113.27; MS m/z 460 (M+1).

EXAMPLE 90N¹-{4-[2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl}-N³,N³-dimethylpropane-1,3-diamine

a) 1-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone

To a solution of 4-fluoroacetophenone (13.8 g, 0.100 mol) and2-chloro-5-trifluoromethylpyridine (20.0 g, 0.110 mol) intetrahydrofuran (400 mL) was added sodium hydride (95%, 5.56 g, 0.220mol) in several portions. The reaction was stirred at room temperaturefor 72 h then carefully quenched by the addition of water (300 mL) anddiethyl ether (200 mL). The organic layer was separated and extractedwith 6N hydrochloric acid (2×300 mL). The aqueous extracts were cooledto 0° C. and 6N sodium hydroxide was used to adjust the solution topH12. The mixture was then extracted with diethyl ether and the combinedorganic extracts were dried over magnesium sulfate. The drying agent wasremoved by filtration and the filtrate was evaporated to dryness toafford the title compound as a tautomeric mixture, 20.9 g (73%). ¹H NMR(CDCl₃): δ 8.87 (s), 8.63 (s), 8.14 (dd, J=5.1, 8.4 Hz), 8.00-7.83 (m),7.51 (d, J=8.4 Hz), 7.22-7.12 (m), 6.13 (s), 4.60 (s). MS (ES+ve): 284(M+1).

b) 1-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone Oxime

To a solution of1-(4-fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone (80.0 g,0.282 mol) in methanol (1 L) at room temperature was added 10% aqueoussodium hydroxide (436 mL, 1.09 mol). The resulting solution was stirredvigorously as solid hydroxylamine hydrochloride (98.0 g; 1.40 mol) wasadded. The mixture was heated to reflux for 2 h, treated withdecolorizing charcoal while hot, then filtered through Celite while hot.The filtrate was concentrated to one-half its original volume and thencooled to 0° C. with stirring for one hour. The resulting solids werecollected by filtration, washed with water, and dried under vacuum at50° C. overnight to provide the title compound as a light yellow powder,73.9 g (88%). ¹H NMR (DMSO-d₆): δ 11.60 (s, 1H), 8.86 (s, 1H), 8.14 (dd,1H, J=2.1, 8.1 Hz), 7.78 (dd, 2H, J=5.7, 9.0 Hz), 7.53 (d, 1H, J=8.4Hz), 7.23 (t, 2H, J=9.0 Hz), 4.40 (s, 2H). MS (ES+ve): 299 (M+1).

c) 3-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl) pyridyl)-2H-azirine

To a solution of1-(4-fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)ethanone oxime (25.0g, 0.084 mol) in methylene chloride (400 mL) was added triethylamine(46.7 mL, 0.335 mol). The solution was cooled to 0° C. under a nitrogenatmosphere, and trifluoroacetic anhydride (14.1 mL, 0.100 mol) was addeddropwise. The reaction was stirred for 0.5 h then quenched with water.The organic layer was separated and dried over anhydrous magnesiumsulfate. The drying agent was removed by filtration and the solvent wasevaporated from the filtrate to leave an oil. The residue was loadedonto a silica gel column and eluted with 15% ethyl acetate in hexanes togive the title compound as an oil which solidified on standing, 19.4 g(82%). ¹H NMR (CDCl₃): δ 8.76 (s, 1H), 7.93 (dd, 2H, J=5.4, 8.7 Hz),7.83 (dd, 1H, J=2.1, 8.4 Hz), 7.27 (t, 2H, J=8.7 Hz), 7.21 (d, 1H. J=8.1Hz), 3.54 (s, 1H). MS (ES+ve): 281 (M+1).

d) 2-(4-Fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

3-(4-Fluorophenyl)-2-(2-(5-trifluoromethyl)pyridyl)-2H-azirine (40.0 g,0.143 mol) was dissolved in 1,2,4-trichlorobenzene (400 mL) and themixture was heated to 200° C. for 10 h. The reaction mixture was thencooled to room temperature and poured onto a silica gel column. Thecolumn was eluted with hexanes to remove the 1,2,4-trichlorobenzene, andthen with 20% diethyl ether in hexanes to elute the product. The desiredfractions were combined and the solvent was evaporated under reducedpressure to leave the title compound, 28.7 g (71%). ¹H NMR (CDCl₃): δ8.84 (s, 1H), 7.98 (dd, 2H, J=5.4, 8.7 Hz), 7.65 (d, 1H, J=9.3 Hz), 7.28(d, 1H, J=9.3 Hz), 7.20 (t, 2H, J=8.7 Hz), 6.88 (s, 1H). MS (ES+ve): 281(M+1).

e) 2-(4-Fluorophenyl)-3-acetyl-6-trifluoromethylpyrazolo[1,5-a]pyridine

To a mixture of2-(4-fluorophenyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine (10.30 g,36.76 mmol) and acetic anhydride (100 mL) was added conc. sulfuric acid(10 drops) and the mixture was stirred and heated at reflux for 1 h. Thereaction mixture was cooled to room temperature and poured into icewater (300 mL). 2N Aqueous sodium hydroxide solution was added to raisethe pH of the solution to about 10 and the resulting orange precipitatewas collected by filtration. The solid was washed with water, air-dried,and then dried under vacuum to afford the title compound as an orangesolid, 11.87 g (quant.). ¹H NMR (DMSO-d6) δ 9.58 (s, 1H), 8.41 (d, 1H,J=9.3 Hz), 7.89 (d, 1H, J=9.5 Hz), 7.74 (m, 2H), 7.39 (m, 2H), 2.22 (s,3H). MS 323 (M+1).

f)2-(4-Fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine

A mixture of2-(4-fluorophenyl)-3-acetyl-6-trifluoromethylpyrazolo[1,5-a]pyridine(11.85 g, 36.77 mmol) and N,N-dimethylformamide dimethyl acetal (100 mL)was stirred at reflux for 17 h. The mixture was cooled to roomtemperature and then to 0° C. The resulting orange precipitate wascollected by filtration, washed with cold hexanes, and dried undervacuum to afford the title compound as an orange solid, 10.17 g (73%).¹H NMR (DMSO-d6) δ 9.44 (s, 1H), 8.22 (d, 1H, J=9.4 Hz), 7.75 (m, 2H),7.65 (d, 1H, J=9.5 Hz), 7.56 (d, 1H, J=12.4 Hz), 7.35 (m, 2H), 5.05 (d,1H, J=12.3 Hz), 3.04 (s, 3H), 2.56 (s, 3H). MS 377 (M+1).

g)N-[3-(dimethylamino)propyl]-N-[4-{2-(4-fluorophenyl)-6-(trifluoromethyl)-pyrazolo[1,5-a]pyridin-3-yl}pyrimidin-2-yl]amine

To a mixture of2-(4-fluorophenyl)-3-(3-(dimethylamino)-2-propenoyl)-6-trifluoromethylpyrazolo[1,5-a]pyridine(2.52 g, 6.68 mmol) and N-(3-dimethylaminopropyl)guanidine (3.23 g, 2.0equiv, 13.4 mmol) in anhydrous tetrahydrofuran (50 mL) under nitrogenwas added a solution of potassium t-butoxide in t-butanol (26.7 mL, 4.0equiv, 26.7 mmol). The mixture was stirred and heated at reflux forabout 17 h and then was allowed to cool to room temperature. Water (50mL) and diethyl ether (100 mL) were added and the organic phase wasseperated. The aqueous phase was extracted with 25%tetrahydrofuran/ether. The combined organic phases were dried overanhydrous sodium sulfate and activated carbon. The drying agents wereremoved by filtration and the filtrate was concentrated to give thetitle compound as a light yellow solid 2.9 g, (95%). ¹H NMR (400 MHz,CDCl₃) δ 1.89 (m, 2H), 2.37, (s, 6H), 2.58 (br, 2H), 3.55 (dd, 2H,J=6.4, 12.4 Hz), 5.87 (br, 1H), 6.30 (d, 1H, J=5.2 Hz), 7.12 (t, 2H,J=8.4 Hz), 7.40 (d, 1H, J=9.2 Hz), 7.58 (dd, 2H, J=5.6, 8.8 Hz), 8.06(d, 1H, J=5.2 Hz), 8.46 (d, 1H, J=9.6 Hz), 8.79 (s, 1H). MS m/z 459.50(M+1).

EXAMPLE 913-(2-Butoxypyridin-4-yl)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine

In a similar manner as described previously, using 1-butanol in place ofan amine, was obtained the title compound. ¹H NMR (acetone-d₆): δ 8.70(d, 1H, J=7.2 Hz), 8.16 (d, 1H, J=5.4 Hz), 7.76 (d, 1H, J=9.0 Hz), 7.68(m, 2H), 7.40 (dd, 1H, J=6.9, 8.7 Hz), 7.23 (m, 2H), 7.06 (dt, 1H,J=6.9, 1.2 Hz), 6.80 (dd, 1H, J=5.4, 1.5 Hz), 6.77 (s, 1H), 4.36(t, 2H,J=6.6 Hz), 1.77(quint, 2H, J=3.9 Hz), 1.5 (sext, 2H, J=7.5 Hz), 1.0 (t,3H, J=7.5 Hz). MS m/z: 362 (M+1).

EXAMPLE 92N-Cyclopentyl-4-[2-(2,4-dimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine

In a similar manner as described aboveN-cyclopentyl-4-[2-(2,4-dimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-aminewas obtained: ¹H NMR (CDCl3): δ 8.57 (d, 1H), 8.49 (d, 1H), 7.97 (d,1H), 7.37 (d, 1H), 7.26 (m, 1H), 6.86 (m, 1H), 6.59 (d, 1H), 6.54 (s,1H), 6.25 (d, 1H), 5.05 (d, 1H), 4.35 (m, 1H), 3.87 (s, 3H), 3.60 (s,3H), 2.1-1.5 (m, 8H); MS m/z:416 (M+1).

EXAMPLE 93 5-Bromo-4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl pyrimidin-2-amine

Treatment of4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentylpyrimidin-2-amine(100 mg, 0.25 mmol) with N-bromosuccinimide (44 mg, 0.25 mmol) indichloromethane (5 mL) gave after workup 110 mg (90%) of the titlecompound as a solid: ¹H NMR (CDCl₃): δ 8.46 (d, 1H), 8.39 (s, 1H), 7.63(m, 3H), 7.11 (t, 2H), 6.87 (dd, 1H), 5.25 (d, 1H), 4.25 (m, 1H),2.1-1.5 (m, 8H); ¹⁹F NMR (CDCl₃): 6-113.0; MS m/z: 487 (M+1).

EXAMPLE 94N-Cyclopentyl-6-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-4-amine

The title compound was synthesized as described previously to give:R_(f) 0.22 (2:1 hexanes:ethyl acetate); ¹H NMR (CDCl₃) δ 8.58 (s, 1H),8.47 (d, 1H), 8.44 (d, 1H), 7.63 (m, 2H), 7.28 (t, 1H), 7.14 (t, 2H),6.88 (t, 1H), 6.08 (s, 1H), 5.21 (br, 1H), 3.52 (m, 1H), 1.77-1.53 (m,6H), 1.35-1.29 (m, 2H); MS m/z 374 (M+1).

EXAMPLE 95N-Cyclopropyl-4-[2-(4-methoxyphenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine

The title compound was synthesized as described previously to give: ¹HNMR: δ 8.85 (s, 1H), 8.73 (d, 1H), 8.09 (d, 1H), 7.58 (d, 2H), 7.45 (d,1H), 7.02 (d, 2H), 6.49 (d, 1H), 5.68 (broad, 1H), 3.90 (s, 3H), 2.89(m, 1H), 0.92 (m, 2H), 0.69 (m, 2H); ¹⁹F NMR: 6-62.66; MS m/z 425 (M+1).

EXAMPLE 96N-Cyclopropyl-4-[2-(4-methoxyphenyl)-6-(triethoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine

The title compound was synthesized as described previously to give: ¹HNMR: δ 8.86 (s, 1H), 8.64 (d, 1H), 8.09 (d, 1H), 7.61 (d, 2H), 7.50 (d,1H), 7.03 (d, 2H), 6.50 (d, 1H), 5.64 (broad, 1H), 3.92 (s, 3H), 3.46(q, 6H), 2.93 (m, 1H), 1.25 (t, 9H), 0.95 (m, 2H), 0.71 (m, 2H); MS m/z504 (M+1).

EXAMPLE 97 Ethyl3-[2-(cyclopropylamino)pyrimidin-4-yl]-2-(4-methoxyphenyl)-pyrazolo[1,5-a]pyridine-6-carboxylate

The title compound was synthesized as described previously to give: ¹HNMR: δ 9.21 (s, 1H), 8.58 (broad, 1H), 8.09 (d, 1H), 7.83 (d, 2H), 7.58(d, 2H), 6.99 (d, 2H), 6.46 (d, 1H), 5.49 (broad, 1H), 4.43 (q, 2H),3.88 (s, 3H), 2.87 (m, 1H), 1.42 (t, 3H), 0.89 (m, 2H), 0.65 (m, 2H); MSm/z 430 (M+1).

EXAMPLE 983-[2-(Cyclopropylamino)pyrimidin-4-yl]-N-(2-methoxyethyl)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-6-carboxamide

The title compound was synthesized as described previously to give: ¹HNMR: δ 9.03 (s, 1H), 8.60 (broad, 1H), 8.09 (d, 1H), 7.61-7.55 (m, 3H),6.99 (d, 2H), 6.51 (broad, 1H), 6.46 (d, 1H), 5.42 (broad, 1H), 3.88 (s,3H), 3.69 (q, 2H), 3.59 (q, 2H), 3.41 (s, 3H), 2.86 (m, 1H), 0.88 (m,2H), 0.65 (m, 2H); MS m/z 459 (M+1).

EXAMPLE 994-{5-Chloro-2-[4-(cyclopropylmethoxy)phenyl]pyrazolo[1,5-a]pyridin-3-yl}-N-cyclopropyl-2-pyrimidinamine

The title compound was synthesized as described previously to give: ¹HNMR CDCl₃ δ 8.80 (broad s, 1H), 8.39 (d, 1H), 8.05 (d, 1H), 7.53 (d,2H), 6.98 (d, 2H), 6.85 (dd, 1H), 6.42 (d, 1H), 5.41 (s, 1H), 3.87 (d,2H), 2.87 (m, 1H), 1.30 (m, 1H), 0.93 (m, 2H), 0.85 (m, 2H), 0.67 (m,2H), 0.39 (m, 2H). MS m/432 (M+1).

EXAMPLES 100-227

Using the techniques described above for Examples 1-99, the followingadditional compounds are prepared. Example No. Structure 100

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EXAMPLE 2284-[7-Butoxy-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

The title compound was prepared in a similar manner as described inabove examples to give a yellow solid. ¹H NMR (CDCl₃): δ 8.08 (d, 1H),8.02 (d, 1H), 7.59 (d, 2H), 7.30 (m, 1H), 6.97 (d, 2H), 6.34 (d, 1H),6.23 (d, 1H), 5.13 (d, 1H), 4.41-4.34 (m, 3H), 3.87 (s, 3H), 2.10 (m,2H), 1.99 (m, 2H), 1.80-1.54 (m, 8H), 1.02 (t, 3H); MS m/z 458 (M+1).

EXAMPLE 2294-[5-Chloro-2-(3-chlorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine

The title compound was prepared in a similar manner as described inabove examples to give a yellow solid. R_(f) 0.23 (4:1 hexanes:ethylacetate); ¹H NMR (CDCl₃) δ 8.37 (s, 1H), 8.02 (d, 1H), 7.70 (s, 1H),7.50 (d, 1H), 7.45-7.33 (m, 2H), 6.61 (s, 1H), 6.29 (d, 1H), 5.20 (d,1H), 4.36 (m, 1H), 2.65 (s, 3H), 2.15 (m, 2H), 1.84-1.52 (m, 6H); MS m/z470 (M+1).

EXAMPLE 230N-cyclopentyl-6-[2-(4-fluorophenyl)-7-(methylthio)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-4-amine

The title compound was prepared in a similar manner as described inabove examples to give a peach colored solid. ¹H NMR (CDCl₃) δ 8.60 (s,1H), 8.26 (d, 1H), 7.86 (m, 2H), 7.32 (t, 1H), 7.15 (t, 2H), 6.70 (d,1H), 6.08 (s, 1H), 4.95 (br, 1H), 3.58 (br, 1H), 2.65 (s, 3H), 1.85-1.50(m, 6H), 1.38-1.22 (m, 2H); MS m/z 420 (M+1).

EXAMPLE 231N-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylthio)-5-morpholin-4-ylpyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine

In a similar manner as described for above examples the title compoundwas prepared as a solid. ¹H NMR (CDCl₃): δ 8.01 (d, 1H), 7.64 (m, 3H),7.15 (t, 2H), 6.45 (d, 1H), 6.26 (d, 1H), 5.17 (d, 1H), 4.46 (m, 1H),3.93 (m, 4H), 3.33 (m, 4H), 2.66 (s, 3H), 2.1-1.5 (m, 8H); ¹⁹F NMR(CDCl₃): δ −113.5; MS m/z 505 (M+1).

EXAMPLE 232N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(isopropylthio)-5-morpholin-4-ylpyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine

In a similar manner as described for above examples the title compoundwas prepared as a solid. ¹H NMR (CDCl₃): δ 8.01 (d, 1H), 7.66 (m, 3H),7.15 (t, 2H), 6.71 (d, 1H), 6.27 (d, 1H), 5.21 (d, 1H), 4.44 (m, 1H),3.93 (m, 4H), 3.31 (m, 4H), 2.1-1.5 (m, 9H), 1.44 (d, 6H); ¹⁹F NMR(CDCl₃): δ −113.6; MS m/z 534 (M+1).

EXAMPLE 233 Biological Activity

In the following example, “MEM” means Minimal Essential Media; “FBS”means Fetal Bovine Serum; “NP40” and “Igepal” are detergents; “MOI”means Multiplicity of Infection; “NaOH” means sodium hydroxide; “MgCl₂”means magnesium chloride; “dATP” means deoxyadenosine 5′ triphosphate;“dUTP” means deoxyuridine 5′ triphosphate; “dCTP” means dexoxycytidine5′ triphosphate; “dGTP” means deoxyguanosine 5′ triphosphate; “GuSCN”means Guanidinium thiocyanate; “EDTA” means ethylenediamine tetraaceticacid; “TE” means Tris-EDTA; “SCC” means sodium chloride/sodium citrate;“APE” means a solution of ammonia acetate, ammonia phosphate, EDTA;“PBS” means phosphate buffered saline; and “HRP” means horseradishperoxidase.

a) Tissue Culture and HSV Infection.

Vero 76 cells were maintained in MEM with Earle's salts, L-glutamine, 8%FBS (Hyclone, A-1111-L) and 100 units/mL Penicillin-100 μg/mLStreptomycin. For assay conditions, FBS was reduced to 2%. Cells areseeded into 96-well tissue culture plates at a density of 5×10⁴cells/well after being incubated for 45 min at 37° C. in the presence ofHSV-1 or HSV-2 (MOI=0.001). Test compounds are added to the wells andthe plates are incubated at 37° C. for 40-48 hours. Cell lysates areprepared as follows: media was removed and replaced with 150 μL/well 0.2N NaOH with 1% Igepal CA 630 or NP-40. Plates were incubated up to 14days at room temperature in a humidified chamber to prevent evaporation.

(b) Preparation of Detection DNA.

For the detection probe, a gel-purified, digoxigenin-labeled, 710-bp PCRfragment of the HSV UL-15 sequence was utilized. PCR conditions included0.5 μM primers, 180 μM dTTP, 20 μM dUTP-digoxigenin (Boehringer Mannheim1558706), 200 μM each of dATP, dCTP, and dGTP, 1×PCR Buffer II (PerkinElmer), 2.5 mM MgCl₂, 0.025 units/μL of AmpliTaq Gold polymerase (PerkinElmer), and 5 ng of gel-purified HSV DNA per 100 μL Extension conditionswere 10 min at 95° C., followed by 30 cycles of 95° C. for 1 min, 55° C.for 30 sec, and 72° C. for 2 min. The amplification was completed with a10-min incubation at 72° C. Primers were selected to amplify a 728 bpprobe spanning a section of the HSV1 UL15 open reading frame(nucleotides 249-977). Single-stranded transcripts were purified withPromega M13 Wizard kits. The final product was mixed 1:1 with a mixtureof 6 M GuSCN, 100 mM EDTA and 200 μg/mL herring sperm DNA and stored at4° C.

(c) Preparation of Capture Plates.

The capture DNA plasmid (HSV UL13 region in pUC) was linearized bycutting with Xba I, denatured for 15 min at 95° C. and dilutedimmediately into Reacti-Bind DNA Coating Solution (Pierce, 17250,diluted 1:1 with TE buffer, pH 8) at 1 ng/μL. 75 μL/well were added toCorning (#3922 or 9690) white 96-well plates and incubated at roomtemperature for at least 4 hrs before washing twice with 300 μL/well0.2×SSC/0.05% Tween-20 (SSC/T buffer). The plates were then incubatedovernight at room temperature with 150 μL/well 0.2 N NaOH, 1% IGEPAL and10 μg/mL herring sperm DNA.

(d) Hybridization

Twenty-seven (27) μL of cell lysate was combined with 45 μL ofhybridization solution (final concentration: 3M GuSCN, 50 mM EDTA, 100μg/ml salmon sperm DNA, 5×Denhardt's solution, 0.25×APE, and 5 ng of thedigoxigenin-labeled detection probe). APE is 1.5 M NH₄-acetate, 0.15 MNH₄H₂ phosphate, and 5 mM EDTA adjusted to pH 6.0. Mineral oil (50 μL)was added to prevent evaporation. The hybridization plates wereincubated at 95° C. for 10 minutes to denature the DNA, then incubatedat 42° C. overnight. The wells were washed 6× with 300 μL/well SSC/Tbuffer then incubated with 75 μL/well anti-digoxigenin-HRP-conjugatedantibody (Boehringer Mannheim 1207733, 1:5000 in TE) for 30 min at roomtemperature. The wells were washed 6× with 300 μL/well with PBS/0.05%Tween-20 before 75 μL/well SuperSignal LBA substrate (Pierce) was added.The plates were incubated at room temperature for 30 minutes andchemiluminescence was measured in a Wallac Victor reader.

e) Results.

The following results were obtained for HSV-1. Example No. IC₅₀ (μM) 10.7 2 1.6 3 1.5 4 20 5 5 6 4.2 7 6.2 8 2.8 9 2.4 11 4.4 12 3.9 13 1.2 142 15 4 16 >20 17 1.5 18 5.4 19 >40 20 16 21 0.8 22 4.3 23 1 24 0.2 255.5 26 0.15 27 0.5 28 0.73 29 10 30 4 31 1.7 32 10 33 2.5 34 2 35 4.5 365 37 1.4 38 3.8 39 1.7 40 5.3 41 21.6 42 5 43 2.4 44 6.3 45 2.6 47 1 480.9 49 2.9 57 2.5 59 10 60 5 62 2 64 0.9 66 25 67 15 68 15 83 1 84 0.685 1 86 6 87 3 88 15 89 3.6 90 1.9 91 11 92 20 93 2.6 95 27 96 5.5 97 1698 1.1 228 0.28 229 1.0 230 1.3 231 0.5 232 0.9

The results demonstrate that the compounds of the present invention areuseful for the treatment and prophylaxis of herpes viral infections.

1. A method for the prophylaxis or treatment of a herpes viral infectionin an animal, said method comprising administering to the animal atherapeutically effective amount of a compound of formula (I):

wherein: Z is CH or N; a is 1 or 2; b is 1, 2 or 3; c is 1, 2 or 3; eachR¹ is independently selected from group consisting of substituents ofthe formula—(X)_(d)—(CH₂)_(e)—R⁵ wherein d is 0 or 1; e is 0 to 6; X is selectedfrom the group consisting of O, NR⁶ and S(O)_(f) where f is 0, 1 or 2;R⁵ is selected from the group consisting of H, halo, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,hydroxyl, cyano, nitro, trihalomethyl, NR⁷R⁸, C₆H₄NR⁷R⁸, C₆H₄(CH₂)NR⁷R⁸,C(O)R⁷, C(O)NR⁷R⁸, OC(O)R⁷, OC(O)NR⁷R⁸, CO₂R⁷, OCO₂R⁷, SO₂R⁷, SO₂NR⁷R⁸,C(═NR⁷)NR⁷R⁸, N(R⁷) [(C═NR⁷)NR⁷R⁸], NHC(O)R⁷ and N(C₁₋₃alkyl)C(O)R⁷;each R² is independently selected from the group consisting of H, cyano,halo, trihalomethyl, OC₁₋₆alkyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,S(O)_(g)C₁₋₆alkyl where g is 0, 1 or 2, NC₁₋₆alkyl(C₁₋₆alkyl), hydroxyland nitro; each R⁴ is independently selected from the group consistingof substituents of the formula—(Y)_(d)—(CH₂)_(e)—R³ wherein d is 0 or 1; e is 0 to 6; Y is O orS(O)_(f) where f is 0, 1 or 2; R³ is selected from the group consistingof H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, hydroxyl, cyano, nitro, trihalomethyl,phthalamido, C₆H₄NR⁷R⁸, C₆H₄(CH₂)NR⁷R⁸, C(O)R⁷, C(O)NR⁷RB, OC(O)R⁷,OC(O)NR⁷R⁸, CO₂R⁷, OCO₂R⁷, SO₂R⁷, SO₂NR⁷R⁸ and C(═NR⁷)NR⁷R⁸; R⁶ isselected from the group consisting of H, C₁₋₆alkyl, C₂₋₆alkenyl,heteroaryl, cycloalkyl, and heterocyclyl; R⁷ and R⁸ are eachindependently selected from the group consisting of H, C₁₋₈alkyl,C₂₋₆alkenyl, SO₂C₁₋₆alkyl, (CH₂)_(m)-cycloalkyl, (CH₂)_(m)-aryl,(CH₂)_(m)-heterocyclyl and (CH₂)_(m)-heteroaryl, wherein m is 0, 1 or 2,or R⁷ and R⁸ together with the nitrogen atom to which they are bound,form a heterocyclyl group; and wherein any of said alkyl, alkenyl andalkynyl groups may be optionally substituted with up to three membersselected from the group consisting of halo, hydroxyl, oxo, cyano, NR⁷R⁸,C₁₋₆alkyl, OC₁₋₆alkyl, S(O)C₁₋₆alkyl, S(O)₂C₁₋₆alkyl and SO₂NR⁷R⁸; andwherein any of said cycloalkyl, heterocyclyl, aryl and heteroaryl groupsmay be optionally substituted with up to three substituents selectedfrom the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkylsulfenyl,C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl, hydroxy, oxo, mercapto, nitro,cyano, halogen, C₁₋₆perfluoroalkyl, amino optionally substituted byC₁₋₆alkyl, carbamoyl optionally substituted by C₁₋₆alkyl, NR⁷R⁸, carboxyand aminosulfonyl optionally substituted by C₁₋₆alkyl; wherein when(R¹)_(a) is located at the 2′ position, (R¹)_(a) is not NR⁶-aryl,NR⁶—C₆H₄NR⁷R⁸, NR⁶—C₆H₄(CH₂)NR⁷R⁸, NR⁷R⁸ where R⁷ or R⁸ is(CH₂)_(m)-aryl and m is O, or N-(aryl)[(C═NR⁷)NR⁷R⁸]; and wherein whenR⁴ is at the C-7 position, R⁴ is not halo, heterocyclyl, aryl,heteroaryl, phthalamido, C₆H₄NR⁷R⁸ or C₆H₄(CH₂)NR⁷R⁸; or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof.
 2. The method according to claim 1 wherein saidherpes viral infection is selected from the group consisting of herpessimplex virus 1, herpes simplex virus 2, cytomegalovirus, Epstein Barrvirus, varicella zoster virus, human herpes virus 6, human herpes virus7, and human herpes virus
 8. 3. A method for the prophylaxis ortreatment of a condition or disease associated with a herpes viralinfection in an animal, comprising administering to the animal atherapeutically effective amount of a compound of formula (I):

wherein: Z is CH or N; a is 1 or 2; b is 1, 2 or 3; c is 1, 2 or 3; eachR¹ is independently selected from the group consisting of substituentsof the formula—(X)_(d)—(CH₂)_(e)—R⁵ wherein: d is 0 or 1; e is 0 to 6; X is selectedfrom the group consisting of O, NR⁶ and S(O)_(f) where f is 0, 1 or 2;R⁵ is selected from the group consisting of H, halo, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,hydroxyl, cyano, nitro, trihalomethyl, NR⁷R⁸, C₆H₄NR⁷R⁸, C₆H₄(CH₂)NR⁷R⁸,C(O)R⁷, C(O)NR⁷R⁸, OC(O)R⁷, OC(O)NR⁷R⁸, CO₂R⁷, OCO₂R⁷, SO₂R⁷, SO₂NR⁷R⁸,C(═NR⁷)NR⁷R⁸, N(R⁷)[(C═NR⁷)NR⁷R⁸], NHC(O)R⁷ and N(C₁₋₃alkyl)C(O)R⁷; eachR² is independently selected from the group consisting of H, cyano,halo, trihalomethyl, OC₁₋₆alkyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,S(O)_(g)C₁₋₆alkyl where g is 0, 1 or 2, NC₁₋₆alkyl(C₁₋₆alkyl), hydroxyland nitro; each R⁴ is independently selected from the group consistingof substituents of the formula—(Y)_(d)—(CH₂)_(e)—R³ wherein: d is 0 or 1; e is 0 to 6; Y is O orS(O)_(f) where f is 0, 1 or 2; R³ is selected from the group consistingof H, halo, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, cycloalkyl,heterocyclyl, aryl, heteroaryl, hydroxyl, cyano, nitro, trihalomethyl,phthalamido, C₆H₄NR R⁸, C₆H₄(CH₂)NR⁷R⁸, C(O)R⁷, C(O)NR⁷R⁸, OC(O)R⁷,OC(O)NR R⁸, CO₂R⁷, OCO₂R⁷, SO₂R⁷, SO₂NR⁷R⁸ and C(═NR⁷)NR⁷R⁸; R⁶ isselected from the group consisting of H, C₁₋₆alkyl, C₂₋₆alkenyl,heteroaryl, cycloalkyl, and heterocyclyl; R⁷ and R⁸ are eachindependently selected from the group consisting of H, C₁₋₈alkyl,C₂₋₆alkenyl, SO₂C₁₋₆alkyl, (CH₂)_(m)-cycloalkyl, (CH₂)_(m)-aryl,(CH₂)_(m)-heterocyclyl, and (CH₂)_(m)-heteroaryl, wherein m=0, 1 or 2,or R⁷ and R⁸ together with the nitrogen atom to which they are bound,form a heterocyclyl group; and wherein any of said alkyl, alkenyl andalkynyl groups may be optionally substituted with up to three membersselected from the group consisting of halo, hydroxyl, oxo, cyano, NR⁷R⁸,C₁₋₆alkyl, OC₁₋₆alkyl, S(O)C₁₋₆alkyl, S(O)₂C₁₋₆alkyl and SO₂NR⁷R₈; andwherein any of said cycloalkyl, heterocyclyl, aryl, and heteroarylgroups may be optionally substituted with up to three substituentsselected from the group consisting of C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkylsulfenyl, C₁₋₆alkylsulfinyl, C₁₋₆alkylsulfonyl, hydroxy, oxo,mercapto, nitro, cyano, halo, C₁₋₆perfluoroalkyl, amino optionallysubstituted by C₁₋₆alkyl, carbamoyl optionally substituted by C₁₋₆alkyl,NR⁷R⁸, carboxy and aminosulfonyl optionally substituted by C₁₋₆alkyl;wherein when (R¹)_(a) is located at the 2′ position, (R¹)_(a) is notNR⁶-aryl, NR⁶—C₆H₄NR⁷R⁸, NR⁶—C₆H₄(CH₂)NR⁷R⁸, NR⁷R⁸ where R⁷ or R⁸ is(CH₂)_(m)-aryl and m is O, or N-(aryl)[(C═NR⁷)NR⁷R⁸]; and wherein whenR⁴ is at the C-7 position, R⁴ is not halo, heterocyclyl, aryl,heteroaryl, phthalamido, C₆H₄NR⁷R⁸ or C₆H₄(CH₂)NR⁷R⁸; or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof. 4-5. (canceled)